Quinoline derivatives

ABSTRACT

NK 3  receptor antagonists of formula (I): 
                         
are useful in treating inter alia pulmonary disorders, CNS disorders and neurodegenerative disorders.

This application is a continuation application of U.S. Ser. No. 10/999,180 filed Nov. 29, 2004, now abandoned, which is a continuation of U.S. Ser. No. 09/867,133 filed May 29, 2001, now abandoned, which is a divisional application of U.S. Ser. No. 08/450,437 filed May 25, 1995, now granted as U.S. Pat. No. 6,608,083.

The present invention relates to novel quinoline derivatives, processes for their preparation and their use in medicine.

The mammalian peptide Neutokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also include Substance P(SP) and Neurokinin A (NKA). Pharmacolooical and molecular biological evidence has shown the existence of three subtypes of TK receptor (NK₁, NK₂ and NK₃) and NKB binds preferentially to the NK₃ receptor although it also recognises the other two receptors with lower affinity (Maggi et al, 1993, J. Auton. Pharmacol., 13, 23-93).

Selective peptidic NK₃ receptor antagonists are known (Drapeau, 1990 Regul. Pept., 31, 125-135), and findings with peptidic NK₃ receptor agonists suggest that NKB, by activating the NK₃ receptor, has a key role in the modulation of neural input in airways, skin, spinal cord and nigro-striatal pathways (Myers and Undem, 1993, J. Phisiol., 470, 665-679; Counture et al., 1993, Regul. Peptides, 46, 426-429; Mccarson and Krause, 1994, J. Neurosci., 14 (2), 712-720; Arenas et al. 1991, J. Neurosci., 11, 2332-8).

However, the peptide-like nature of the known antagonists makes them likely to be too labile from a metabolic point of view to serve as practical therapeutic agents.

We have now discovered a novel class of selective, non-peptide NK₃ antagonists which are far more stable from a metabolic point of view than the known peptidic NK₃ receptor antagonists and are of potential therapeutic utility in treating pulmonary disorders (asthma, chronic obstructive pulmonary diseases -COPD-, airway hyperreactivity, cough), skin disorders and itch (for example, atopic dermatitis and cutaneous wheal and flare), neurogenic inflammation and CNS disorders (Parkinson's disease, movement disorders, anxiety and psychosis). These disorders are referred to hereinafter as the Primary Disorders.

The novel NK₃ antagonists of the present invention are also of potential therapeutic utility in treating convulsive disorders (for example epilepsy), renal disorders, urinary incontinence, ocular inflammation, inflammatory pain, eating disorders (food intake inhibition), allergic rhinitis, neurodegenerative disorders (for example Alzheimer's disease), psoriasis, Huntington's disease, and depression (hereinafter referred to as the Secondary Disorders).

According to the present invention there is provided a compound, or a solvate or salt thereof, of formula (I):

in which:

-   Ar is an optionally substituted phenyl, naphthyl or C₅₋₇     cycloalkdienyl group, or an optionally substituted single or fused     ring heterocyclic group, having aromatic character, containing from     5 to 12 ring atoms and comprising up to four hetero-atoms in the or     each ring selected from S, O, N; -   R is linear or branched C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₄₋₇     cycloalkylalkyl, optionally substituted phenyl or phenyl C₁₋₆ alkyl,     an optionally substituted five-membered heteroaromatic ring     comprising up to four heteroatom selected from O and N, hydroxy C₁₋₆     alkyl, amino C₁₋₆ alkyl, C₁₋₆ alkylaminoalkyl, di C₁₋₆     alkylaminoalkyl, C₁₋₆ acylaminoalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆     alkylcarbonyl, carboxy, C₁₋₆ alkoxyxcarbonyl, C₁₋₆ alkoxycarbonyl     C₁₋₆ alkyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di C₁₋₆     alkylaminocarbonyl, halogeno C₁₋₆ alkyl; or is a group —(CH₂)_(p)—     when cyclized onto Ar, where p is 2 or 3. -   R₁ and R₂, which may be the same or different, are independently     hydrogen or C₁₋₆ linear or branched alkyl, or together form a     —(CH2)_(n)— group in which n represents 3, 4, or 5; or R₁ together     with R forms a group —(CH₂)_(q)—, in which q is 2, 3, 4 or 5. -   R₃ and R₄, which may be the same or different, are independently     hydrogen, C₁₋₆ linear or branched alkyl, C₁₋₆ alkenyl, aryl, C₁₋₆     alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido,     sulphonamido, C₁₋₆ alkoxycarbonyl, trifluoromethyl, acyloxy,     phthalimido, amino, mono- and di-C₁₋₆ alkylamino, —O(CH₂)_(r)—NT₂,     in which r is 2, 3, or 4 and T is hydrogen or C₁₋₆ alkyl or it forms     with the adjacent nitrogen a group

-    in which V and V₁ are independently hydrogen or oxygen and u is 0,     1 or 2; —O(CH₂)_(s)—OW₂ in which s is 2, 3, or 4 and W is hydrogen     or C₁₋₆ alkyl; hydroxyalkyl, aminoalkyl, mono- or     di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino,     mono- or di-alkylaminoacylamino; with up to four R₃ substituents     being present in the quinoline nucleus; or R₄ is a group —(CH₂)_(t)—     when cyclized onto R₅ as aryl, in which t is 1, 2, or 3; -   R₅ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇     cycloalkylalkyl, optionally substituted aryl, or an optionally     substituted single or fused ring heterocyclic group, having aromatic     character, containing from 5 to 12 ring atoms and comprising up to     four hetero-atoms in the or each ring selected from S, O, N; -   X is O, S, or N—C≡N.

Examples of Ar are phenyl, optionally substituted by hydroxy, halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl. Examples of halogen are chlorine and fluorine, an example of C₁₋₆ alkoxy is methoxy and an example of C₁₋₆ alkyl is methyl.

Examples of Ar as a heterocyclic group are thienyl and pyridyl.

Examples of Ar as a C₅₋₇ cycloalkdienyl group is cyclohexadienyl.

Examples of R are as follows:

-   C₁₋₈ alkyl: methyl, ethyl, n-propyl, iso-propyl, n-butyl, heptyl; -   phenyl C₁₋₆ alkyl: benzyl; -   hydroxy C₁₋₆ alkyl: —CH₂OH, —CH₂CH₂OH, CH(Me)OH; -   amino C₁₋₆ alkyl: —CH₂NH₂; -   di C₁₋₆ alkylaminoalkyl: —CH₂NMe₂; -   C₁₋₆ alkoxylalkyl: CH₂OMe; -   C₁₋₆ alkylcarbonyl: COMe; -   C₁₋₆ alkoxycarbonyl: COOMe; -   C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl: CH₂COOMe; -   C₁₋₆ alkylaminocarbonyl: CONHMe; -   di C₁₋₆ alkylaminocarbonyl: CONMe₂, CO(1-pyrrolidinyl); -   halogen C₁₋₆ alkyl: trifluoromethyl; -   —(CH₂)_(p)— when cyclized onto Ar:

Example of R₁ and R₂ as C₁₋₆ alkyl is methyl; example of R₁ together with R forming a group —(CH₂)_(q)— is spirocyclopentane.

Examples of R₃ and R₄ are methyl, ethyl, n-propyl, n-butyl, methoxy, hydroxy, amino, chlorine, fluorine, bromine, acetyloxy, 2-(dimetylamino)ethoxy, 2-(1-phthaloyl)ethoxy, aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, phthaloyl, dimethylaminopropoxy, dimethylaminoacetylamino, acetylamino, dimethylaminomethyl and phenyl.

Examples of R₅ are cyclohexyl, phenyl optionally substituted as defined for Ar above; examples of R₅ as a heterocyclic group are furyl, thienyl, pyrryl, thiazolyl, benzofuryl and pyridyl.

A preferred group of compounds of formula (I) are those in which:

-   -   Ar is phenyl, optionally substituted by C₁₋₆ alkyl or halogen;         thienyl or a C₅₋₇ cycloalkdienyl group;     -   R is C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonyl,         hydroxy C₁₋₆ alkyl;     -   R₁ and R₂ are each hydrogen or C₁₋₆ alkyl;     -   R₃ is hydrogen, hydroxy, halogen, C₁₋₆ alkoxy, C₁₋₆ alkyl;     -   R₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxy, amino,         halogen, aminoalkoxy, mono- or di-alkylaminoalkoxy, mono- or         di-alkylaminoalkyl, phthaloylalkoxy, mono- or         di-alkylaminoacylamino and acylamino;     -   R₅ is phenyl, thienyl, furyl, pyrryl and thiazolyl.

A further preferred group of compounds of formula (I) are those in which:

-   -   Ar is phenyl, 2-chlorophenyl, 2-thienyl or cyclohexadienyl;     -   R is methyl, ethyl, n-propyl, —COOMe, —COMe;     -   R₁ and R₂ are each hydrogen or methyl;     -   R₃ is hydrogen, methoxy, or hydroxy;     -   R₄ is hydrogen, methyl, ethyl, methoxy, hydroxy, amino,         chlorine, bromine, dimethylaminoethoxy, 2-(1-phthaloyl)ethoxy,         aminoethoxy, 2-(1-pyrrolidinyl)ethoxy, dimethylaminopropoxy,         dimethylaminoacetylamino, acetylamino, and dimethylaminomethyl.     -   R₅ is phenyl, 2-thienyl, 2-furyl, 2-pyrryl, 2-thiazolyl and         3-thienyl;     -   and X is oxygen.

A preferred sub-group of compounds within the scope of formula (I) above is of formula (Ia):

in which:

R, R₂, R₃ and R₄ are as defined in formula (I), and Y and Z, which may be the same or different, are each Ar as defined in formula (I).

A particularly preferred group of compounds of formula (Ia) are those of formula (Ib) in which the group R is oriented downward and H upward.

The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. A substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate. One preferred pharmaceutically acceptable form is the crystalline form, including such form in pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic.

Examples of pharmaceutically acceptable salts of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic, and methanesulphonic.

Examples of pharmaceutically acceptable solvates of a compound of formula (I) include hydrates.

The compounds of formula (I) may have at least one asymmetric centre and therefore may exist in more than one stereoisomeric form. The invention extends to all such forms and to mixtures thereof, including racemates.

The invention also provides a process for the preparation of a compound of formula (I) which comprises reacting a compound of formula (III)

in which R′, R′₁, R′₂ and Ar′ are R. R₁, R₂ and Ar as defined for formula (I) or a group or atom convertible to R, R₁, R₂ and Ar, with a compound of formula (II)

or an active derivative thereof, in which R′₃, R′₄, R′₅ and X′ are R₃, R₄, R₅ and X as defined for formula (I) or a group convertible to R₃, R₄, R₅ and X, to form a compound of formula (Ic)

and optionally thereafter performing one or more of the following steps:

(a) where R′, R′₁ to R′₅, Ar′ and X′ are other than R, R₁ to R₅, Ar and X, converting any one of R′, R′₁ to R′₅, Ar′ and X′ to R, R₁ to R₅, Ar and X to obtain a compound of formula (I),

(b) where R′, R′, to R′₅, Ar′ and X′ are R, R₁ to R₅, Ar and X, converting any one of R, R₁ to R₅, Ar and X to another R, R₁ to R₅, Ar and X, to obtain a compound of formula (I),

(c) forming a salt and/or solvate of the obtained compound of formula (Ic).

Suitable active derivatives of the compounds of formula (II) are acid halides (preferably chlorides), acid azides or acid anhydrides. Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chloroformate; another suitable derivative is an activated ester such as a cyanomethyl ester, thiophenyl ester, p-nitrophenyl ester, p-nitrothiophenyl ester, 2,4,6-trichlorophenyl ester, pentachlorophenyl ester, pentafluorophenyl ester, N-hydroxy-phtalimido ester, N-hydroxypiperidine ester, N-hydroxysuccinimide ester, N-hydroxy benzotriazole ester; or the carboxy group may be activated using a carbodiimide or N,N′-carbonyldiimidazole.

For example, in standard methods well known to those skilled in the art, the compounds of formula (III) may be coupled:

(a) with an acid chloride in the presence of an inorganic or organic base in a suitable aprotic solvent such as dimethylformamide (DMF) at a temperature in a range from −70 to 50° C. (preferably in a range from −10 to 20° C.),

(b) with the acid in the presence of a suitable condensing agent, such as for example N,N′-carbonyl diimidazole (CDI) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or N-dimethylaminopropyl-N′-ethylcarbodiimide and N-hydroxybenzotriazole (HOBT) to maximise yields and avoid racemization processes (Synthesis, 453, 1972) in an aprotic solvent such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF) in a ratio from 1:9 to 7:3, respectively, at a temperature in a range from −70 to 50° C. (preferably in a range from −10 to 25° C.) (see Scheme 1),

(c) with a mixed anhydride generated in situ from the acid and an alkyl (for example isopropyl) chloroformate in a suitable aprotic solvent such as dichloromethane at a temperature in a range from −70 to 50° C. (preferably in a range from −20 to 20° C.).

It will be appreciated that a compound of formula (Ic) may be converted to a compound of formula (I), or one compound of formula (I) may be converted to another compound of formula (I), by interconversion of suitable substituents. Thus, certain compounds of formula (I) and (Ic) are useful intermediates in forming other compounds of the present invention.

For example R′₂ may be hydrogen and converted to R₂ alkyl group, for example methyl, by conventional amide alkylation procedures (Zabicky, The chemistry of amides; Interscience, London, 1970, p. 749). When X′ is oxygen, it may be converted to X sulphur by standard thioamide formation reagents, such as P₂S₅ (Chem. Rev., 61, 45, 1961 or Angew. Chem., 78, 517, 1966) or the Lawesson reagent (Tetrahedron, 41, 5061, 1985). When Ar′ or R′₅ is a methoxy substituted phenyl, it may be converted to another Ar′ or R′₅ hydroxy substituted phenyl by standard demethylation procedures via Lewis acids, such as boron tribromide (Synthesis, 249, 1983) or mineral acids, such as hydrobromic or hydroiodic acid. When R is an alkoxycarbonyl group, for example methoxycarbonyl, it may be converted to another R, such as ethoxycarbonyl by transesterification with an appropriate alcohol at a temperature in a range from 20 to 120° C., carboxy by hydrolysis in acidic or basic medium, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl by transamidation with ammonia, a primary amine or a secondary amine in methanol as solvent at a temperature in a range from 10 to 120° C., optionally in the presence of a catalytic amount of NaCN (J. Org. Chem., 52, 2033, 1987) or by using trimethylaluminium (Me₃Al) (Tetrahedron Letters, 48, 4171, 1977), hydroxymethyl by a selective metal hydride reduction, such as lithium borohydride reduction (Tetrahedron, 35, 567, 1979) or sodium borohydride reduction in THF+MeOH (Bull. Chem. Soc. Japan, 57, 1948, 1984 or Synth. Commun., 12, 463, 1982), alkylcarbonyl by acyl chloride formation and subsequent reaction with alkylmagnesium halides in THF as solvent at a temperature in a range from −78 to 30° C. (Tetrahedron Letters, 4303, 1979) or with alkylcadmium halides or dialkylcadmium in the presence of MgCl₂ or LiCl (J. Org. Chem, 47, 2590, 1982). Another group which R′ as methoxycarbonyl can be converted into is a substituted heteroaromatic ring, such as an oxadiazole (J. Med. Chem., 34, 2726, 1991).

Scheme 2 summarizes some of the above described procedures to convert a compound of formula (Ic) or (I) in which X′ is oxygen, R′ is COOMe, Ar′ and R′₁ to R′₅ are as described for formula (I) to another compound of formula (I).

The compounds of formula (I) may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.

Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent. For example, hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.

Also salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.

As mentioned before, the compounds of formula (I) may exist in more than one stereoisomeric form and the process of the invention may produce racemates as well as enantiomerically pure forms. To obtain pure enantiomers, appropriate enantiomerically pure primary or secondary amines of formula (IIId) or (IIIe)

are reacted with compounds of formula (II), to obtain compounds of formula (I′d) or (I′e).

Compounds of formula (I′d) or (I′e) may subsequently be converted to compounds of formula (Id) or (Ie) by the methods of conversion mentioned before.

Compounds of formula (II) are known compounds or can be prepared from known compounds by known methods.

For example, the compound of formula (II), in which X′ is oxygen, R′₃, R′₄ and R′₅ are hydrogen is described in Pfitzinger, J. Prakt. Chem., 38, 582, 1882 and in Pfitzinger, J. Prakt. Chem., 56, 293, 1897; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R₁₅ is 2-pyridyl is described in Risaliti, Ric. Scient., 28, 561, 1958; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R₁₅ is o-, m- and p-chlorophenyl, o-fluorophenyl and 3,4-dichlorophenyl are described in Brown et al., J. Am. Chem. Soc., 68, 2705, 1946; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is p-methoxyphenyl is described in Ciusa and Luzzatto, Gazz, Chim. Ital., 44, 64, 1914; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is m-trifluoromethylphenyl is described in Shargier and Lalezari, J. Chem. Eng. Data, 8, 276, 1963; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is p-fluorophenyl is described in Bu Hoi et al., Rec Trav. Chim, 68, 781, 1949; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R′₅ is p-methylphenyl is described in Prevost et al., Compt. Rend Acad. Sci., 258, 954, 1964; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R₁₅ is p-bromophenyl is described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; the compound of formula (II) in which X′ is oxygen, R′₄ and R′₅ are hydrogen and R₁₃ is 6-methyl is described in Buchmann and Howton, J. Am. Chem. Soc., 68, 2718, 1946; the compound of formula (II), in which X′ is oxygen, R′₄ and R′₅ are hydrogen and R₁₃ is 8-nitro is described in Buchmann et al, J. Am. Chem. Soc., 69, 380, 1947; the compound of formula (II), in which X′ is oxygen, R′₄ is hydrogen, R′₃ is 6-chloro, R₁₅ is p-chlorophenyl is described in Lutz et al., J. Am. Chem. Soc., 68, 1813, 1946; the compound of formula (II), in which X′ is oxygen, R′₃ and R′₄ are hydrogen and R₁₅ is 2-thiazolyl is described in Eur. Pat. Appl. EP 112,776; compounds of formula (II), in which X′ is oxygen, R′₃ is 8-trifluoromethyl, R′₄ is hydrogen and R₁₅ are phenyl, o- and p-fluorophenyl, 3,4 -dichlorophenyl, p-methoxyphenyl are described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; compounds of formula (II), in which X′ is oxygen, R′₃ is 6-bromo, R′₄ is hydrogen and R′₅ are phenyl or p-fluorophenyl are described in Nicolai et al., Eur. J. Med. Chem., 27, 977, 1992; other compounds of formula (II) are described in Ger. Offen. DE 3,721,222 and in Eur. Pat. Appl. EP 384,313.

Compounds of formula (III), (IIId) and (IIIe) are commercially available compounds or can be prepared from known compounds by known methods (for example, compounds of formula (III) in which R′ is alkoxycarbonyl, R′₁ and R′₂ are hydrogen and Ar′ is as defined for the compounds of formula (I), are described in Liebigs Ann. der Chemie, 523, 199, 1936).

The activity of the compounds of formula (I) as NK₃ receptor antagonists in standard tests indicates that they are of potential therapeutic utility in the treatment of both the Primary and Secondary Disorders herein before referred to.

The discovery that NK₃ receptor antagonists have potential therapeutic utility in treating the Secondary Disorders is new, and in a further aspect of the present invention there is provided the use of an NK₃ receptor antagonist for the treatment of the Secondary Disorders. There is also provided the use of an NK₃ receptor antagonist in the manufacture of a medicament for the treatment of any of the Secondary Disorders.

The present invention also provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.

The present invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of the Primary and Secondary Disorders.

Such a medicament, and a composition of this invention, may be prepared by admixture of a compound of the invention with an appropriate carrier. It may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.

These conventional excipients may be employed for example as in the preparation of compositions of known agents for treating the conditions.

Preferably, a pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields. For example, such preparations may be in a pack form accompanied by written or printed instructions for use as an agent in the treatment of the conditions.

The suitable dosage range for the compounds of the invention depends on the compound to be employed and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.

The compound or composition of the invention may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.

Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.

The compositions, for example those suitable for oral administration, may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinyl-pyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.

Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. When the composition is in the form of a tablet, powder, or lozenge, any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.

Compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oral route. In accordance with routine pharmaceutical procedure, the compositions may be formulated, for example for rectal administration as a suppository. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids. The liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives. Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi-dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an injectable formulation.

The compounds of this invention may also be administered by inhalation, via the nasal or oral routes. Such administration can be carried out with a spray formulation comprising a compound of the invention and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.

Preferred spray formulations comprise micronised compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles. Preferably, the compound particle size is from about 2 to 10 microns.

A further mode of administration of the compounds of the invention comprises transdermal delivery utilising a skin-patch formulation. A preferred formulation comprises a compound of the invention dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the compound to diffuse from the adhesive through the skin for delivery to the patient. For a constant rate of percutaneous absorption, pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.

As mentioned above, the effective dose of compound depends on the particular compound employed, the condition of the patient and on the frequency and route of administration. A unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg. Alternatively the unit dose will contain from 2 to 20 mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.

No unacceptable toxicological effects are expected with compounds of the invention when administered in accordance with the invention.

The present invention also provides a method for the treatment and/or prophylaxis of the Primary and Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

The invention further provides a method for the treatment and/or prophylaxis of the Secondary Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of an NK₃ receptor antagonist.

The activity of the compounds of the present invention, as NK₃ ligands, is determined by their ability to inhibit the binding of the radiolabelled NK₃ ligands, [¹²⁵I]-[Me-Phe⁷]-NKB or [³H]-Senktide, to guinea-pig and human NK₃ receptors (Renzetti et al, 1991, Neuropeptide, 18, 104-114; Buell et al, 1992, FEBS, 299(1), 90-95; Chung et al, 1994, Biochem. Biophys. Res. Commun., 198(3), 967-972).

The binding assays utilized allow the determination of the concentration of the individual compound required to reduce by 50% the [¹²⁵I]-[Me-Phe⁷]-NKB and [³H]-Senktide specific binding to NK₃ receptor in equilibrium conditions (IC₅₀). Binding assays provide for each compound tested a mean IC₅₀ value of 2-5 separate experiments performed in duplicate or triplicate. The most potent compounds of the present invention show IC₅₀ values in the range 1-1000 nM; in particular, in guinea-pig cortex membranes by displacement of [³H]-Senktide, the compounds of the Examples 22, 47, 48, and 85 display K_(i)s (nM) of 5.6, 8.8, 12.0 and 4.8 respectively (n=3). The NK₃-antagonist activity of the compounds of the present invention is determined by their ability to inhibit senktide-induced contraction of the guinea-pig ileum (Maggi et al, 1990, Br. J. Pharmacol., 101, 996-1000) and rabbit isolated iris sphincter muscle (Hall et al., 1991, Eur. J. Pharmacol., 199, 9-14) and human NK₃ receptors-mediated Ca⁺⁺ mobilization (Mochizuki et al, 1994, J. Biol. Chem., 269, 9651-9658). Guinea-pig and rabbit in-vitro functional assays provide for each compound tested a mean K_(B) value of 3-8 separate experiments, where K_(B) is the concentration of the individual compound required to produce a 2-fold rightward shift in the concentration-response curve of senktide. Human receptor functional assay allows the determination of the concentration of the individual compound required to reduce by 50% (IC₅₀ values) the Ca⁺⁺ mobilization induced by the agonist NKB. In this assay, the compounds of the present invention behave as antagonists.

The therapeutic potential of the compounds of the present invention in treating the conditions can be assessed using rodent disease models.

The following Descriptions illustrate the preparation of the intermediates, whereas the Examples illustrate the preparation of the compounds of the present invention. The compounds of the Examples are summarised in the Tables 1 to 6

Description 1

2-phenylquinoline-4-carboxylic acid chloride

11.7 ml (136.3 mmol) of oxalyl chloride were dissolved in 150 ml of CH₂Cl₂. The solution was cooled at −10° C. and 20 g (80.2 mmol) of commercially available 2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 22 g of the title compound, used without further purification.

C₁₆H₁₀ClNO M.W.=267.76

Description 2

7-methoxy-2-phenylquinoline-4-carboxylic acid

5 g (28.2 mmol) of 6-methoxyisatin, 4 ml (33.8 mmol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide were dissolved in 22.9 ml of abs. EtOH and the slurry heated at 80° C. for 42 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et₂O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water.

The solid obtained was dried in-vacuo at 40° C. to yield 7.0 g of the tide compound.

C₁₇H₁₃NO₃ M.P.=226-228° C. M.W.=279.30Elemental analysis: Calcd. C, 73.11; H, 4.69; N, 5.01.Found C, 72.07; H, 4.59; N, 4.90.I.R. (KBr): 3420; 1630 cm¹.

Description 3

7-methoxy-2-phenylquinoline-4-carboxylic acid chloride

2.8 ml (32.3 mmol) of oxalyl chloride were dissolved in 60 ml of CH₂Cl₂. The solution was cooled at −10° C. and 6 g (19.0 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 7 g of the title compound, used without further purification.

C₁₇H₁₂ClNO₂M.W.=297.74

Description 4

7-hydroxy-2-phenylquinoline-4-carboxylic acid hydroiodide

1.5 g (5.4 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were, added portionwise to 50 ml of 57% aqueous HI. The reaction mixture was refluxed and vigourously stirred for 5 hours; then it was evaporated in-vacuo to dryness to yield 2.1 g of the title compound.

C₁₆H₁₁NO₃.HI M.W.=393.17I.R. (KBr): 3120; 1650; 1620 cm⁻¹.

Description 5

2-(2-thienyl)quinoline-4-carboxylic acid

5 g (34.0 mmol) of isatin, 4.4 ml (40.8 mmol) of 2-acetylthiophene and 6.3 g (112.2 mmol) of potassium hydroxide were dissolved in 40 ml of abs. EtOH and the slurry heated at 80° C. for 16 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et₂O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water.

The crude product obtained was dried in-vacuo at 40° C. and triturated with EtOAc to yield 4.8 g of the title compound.

C₁₄H₉NO₂S M.P.=181-183° C. M.W.=255.29I.R. (KBr): 1620 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 8.60 (d, 1H); 8.45 (s, 1H); 8.10 (m, 2H); 7.78 (m, 2H); 7.68 (t, 1H); 7.22 (m, 1H).

Description 6

2-(2-furyl)quinoline-4-carboxylic acid

5 g (34.0 mmol) of isatin, 4 ml (40.8 mmol) of 2-acetylfuran and 6.3 g (112.2 mmol) of potassium hydroxide were dissolved in 40.9 ml of abs. EtOH and the slurry heated at 80° C. for 12 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et₂O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water. The crude product obtained was dried in-vacuo at 40° C. to yield 8.5 g of the tide compound.

C₁₄H₉NO₃ M.W.=239.23

Description 7

2-(2-furyl)quinoline-4-carboxylic acid chloride

5.2 ml (60.4 mmol) of oxalyl chloride were dissolved in 70 ml of CH₂Cl₂. The solution was cooled at −10° C. and 8.5 g (35.5 mmol) of 2-(2-furyl)quinoline-4-carboxylic acid were added portionwise. The reaction mixture was left overnight at room temperature and then evaporated to dryness to yield 9.2 g of the title compound, used without further purification.

C₁₄H₈ClNO₂M.W.=257.78

Description 8

2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride

5 g (34.0 mmol) of isatin, 4.5 ml (40.8 mmol) of 4-acetylpyridine and 6.3 g (112.2 mmol) of potassium hydroxide were dissolved in 40 ml of abs. EtOH and the slurry heated at 80° C. for 12 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et₂O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water.

The aqueous solution was evaporated in-vacuo to dryness, the residue triturated with EtOH and filtered off. Evaporation of the solvent afforded 6.0 g of the crude title compound. This product was combined with the previously obtained precipitate and recrystallized from toluene containing traces of MeOH to yield 4.5 g of the title compound.

C₁₅H₁₀N₂O₂.HCl M.P.=297-301° C. M.W.=286.72I.R. (KBr): 1705; 1635; 1610 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 8.90 (d, 2H); 8.70 (m, 2H); 8.50 (s, 2H); 8.28 (d, 1H); 7.89 (dt, 2H).

Description 9

2-(4-pyridyl)quinoline-4-carboxylic acid chloride hydrochloride

1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH₂Cl₂. The solution was cooled at −10° C. and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.

C₁₅H₉ClN₂O.HCl M.W.=305.22

EXAMPLE 1 (R,S)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide

1.2 ml (9.4 mmol) of (R,S) α-methylbenzylamine and 1.6 ml (11.7 mmol) of triethylamine (TEA) were dissolved, under nitrogen athmosphere, in 50 ml of a 1:1 mixture of dry CH₂Cl₂ and CH₃CN.

2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride, dissolved in 50 ml of a 1:4 mixture of dry CH₂Cl₂ and DMF, were added dropwise to the ice-cooled solution of the amines and the reaction was kept at 0°-5° C. for 1 hour and left at room temperature overnight.

The reaction mixture was evaporated in-vacuo to dryness, the residue was dissolved in EtOAc and washed twice with a sat. sol. of NaHCO₃. The organic layer was separated, dried over Na₂SO₄, filtered and evaporated in-vacuo to dryness.

The residual oil was crystallized from EtOAc to yield 1.1 g of the title compound as a white solid.

C₂₄H₂₀N₂O M.P.=156-157° C. M.W.=352.43Elemental analysis: Calcd. C, 81.79; H, 5.72; N, 7.95.Found C, 81.99; H, 5.69; N, 7.89.I.R. (KBr): 3240; 1645 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.29 (d, 1H); 8.32 (d, 2H); 8.13 (d, 1H); 8.13 (s, 1H); 8.06 (d, 1H); 7.81 (ddd, 1H); 7.68-7.52 (m, 4H); 7.47 (d, 2H); 7.39 (dd, 2H); 7.27 (dd, 1H); 5.30 (dq, 1H); 1.52 (d, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 352 (M+.); 337; 232; 204; 77.

EXAMPLE 2 S-(+)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide

Prepared as Ex. 1 from 1.2 ml (9.4 mmol) of S-(−)-α-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA, 2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride in 100 ml of a mixture of CH₂Cl₂, CH₃CN and DMF.

The work-up of the reaction mixture was carried out in the same manner as described in Ex. 1. The residual oil was crystallized from EtOAc to yield 1.1 g of the title compound.

C₂₄H₂₀N₂O M.P.=161-162° C. M.W.=352.43 [α]_(D) ²⁰=+25 (C=0.5, DMF) I.R. (KBr): 3240; 1645 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.29 (d, 1H); 8.32 (d, 2H); 8.13 (d, 1H); 8.13 (s, 1H); 8.06 (d, 1H); 7.81 (ddd, 1H); 7.68-7.52 (m, 4H); 7.47 (d, 2H); 7.39 (dd, 2H); 7.27 (dd, 1H); 5.30 (dq, 1H); 1.52 (d, 3H). MS spactra was identical to that of the Ex. 1.

EXAMPLE 3 R-(−)-N-(α-methylbenzyl)-2-phenylquinoline-4-carboxamide

Prepared as Ex. 1 from 1.2 ml (9.4 mmol) of R-(+)-α-methylbenzylamine, 1.6 ml (11.7 mmol) of TEA and 2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride in 100 ml of a mixture of CH₂Cl₂, CH₃CN and DMF. The work-up of the reaction mixture was carried out in the same manner as described in Ex. 1. The residual oil was crystallized from EtOAc to yield 1.1 g of the title compound.

C₂₄H₂₀N₂O M.P.=158-160° C. M.W.=352.43 [α]_(D) ²⁰=−25 (C=0.5, DMF) I.R. (KBr): 3240; 1645 cm⁻¹.

The ¹H-NMR and MS spectra were identical to those of the Ex. 1 and Ex. 2.

EXAMPLE 4 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide

2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen athmosphere, in 130 ml of dry THF and 100 ml of CH₃CN.

2.0 g (9.9 mmol) of (D,L) methyl phenylglicinate hydrochloride and 1.5 ml (10.7 mmol) of TEA were added and the reaction mixture was cooled at 5° C.

2.5 g (12.1 mmol) of dicyclohexylcarbodiimide (DCC), dissolved in 10 ml of dry CH₂Cl₂, were added dropwise and the solution was allowed to reach room temperature, stirred for 5 hours and left overnight.

The precipitated dicyclohexylurea was filtered off and the solution was evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and then washed with H₂O. The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness to obtain 6.0 g of a crude product which was dissolved in 20 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off.

The solution was evaporated in-vacuo to dryness and the residue flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH₄OH. The crude solid obtained was triturated with warm i-Pr₂O, filtered, washed and dried to yield 1.1 g of the title compound.

C₂₅H₂₀N₂O₃M.P.=170-172° C. M.W.=396.45Elemental analysis: Calcd. C, 75.74; H, 5.09; N, 7.07.Found C, 75.88; H, 5.12; N, 7.06.I.R. (nujol): 3240; 1750; 1670 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.72 (d, 1H); 8.28 (dd, 2H); 8.20 (dd, 1H); 8.13 (dd, 1H); 8.11 (s, 1H); 7.83 (ddd, 1H); 7.66 (ddd, 1H); 7.60-7.50 (m, 5H); 7.47-7.37 (m, 3H); 5.78 (d, 1H); 3.72 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 396 (M+.); 337; 232; 204.

EXAMPLE 5 (+)-(S)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide

2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen athmosphere, in 70 ml of dry THF and 30 ml of CH₃CN.

1.7 g (8.4 mmol) of (L) methyl phenylglicinate hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine and 2.1 g (15.5 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at 0° C.

1.85 g (9.0 mmol) of DCC, dissolved in 10 ml of CH₂Cl₂, were added dropwise and the solution was kept at 0°-5° C. for 1 hour and then at room temperature for 2 hours. The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and sat. sol. NaCl.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off.

The solution was evaporated in-vacuo to dryness to obtain 2.6 g of a crude product which was triturated with petroleum ether, filtered, washed with i-Pr₂O and then recrystallized from 70 ml of i-PrOH to yield 1.7 g of the title compound.

C₂₅H₂₀N₂O₃M.P.=180-181° C. M.W.=396.45I.R. (nujol): 3300; 1750; 1640 cm⁻¹. [α]D²⁰=+42.0 (C=0.5, MeOH).

The ¹H-NMR and MS spectra were identical to those of Ex. 4.

EXAMPLE 6 (−)-(R)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide

Prepared as Ex. 5 from 2.0 g (8.0 mmol) of 2-phenylquinoline-4-carboxylic acid, 1.7 g (8.4 mmol) of (D) methyl phenylglicinate hydrochloride, 1.1 ml (9.9 mmol) of N-methylmorpholine, 2.1 g (15.5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in 70 ml of dry THF and 30 ml of CH₃CN.

The work-up of the reaction mixture was carried out in the same manner as described in Ex. 5. The crude product obtained (3.5 g) was triturated twice with warm i-Pr₂O, filtered, washed and then recrystallized from 80 ml of i-PrOH to yield 2.3 g of the title compound.

C₂₅H₂₀N₂O₃M.P.=180-181° C. M.W.=396.45I.R. (nujol): 3300; 1750; 1640 cm⁻¹. [α]_(D) ²⁰=−42.0 (C=0.5, MeOH).

The ¹H-NMR and MS spectra were identical to those of Exs. 4 and 5.

EXAMPLE 7 5 (R,S)-N-[α-(methoxycarbonyl)benzyl]-7-methoxy-2-phenylquinoline-4-carboxamide

1.0 g (5.0 mmol) of (D,L) methyl phenylglicinate hydrochloride were dissolved, under nitrogen athmosphere, in 30 ml of dry DMF.

2.5 g (18.1 mmol) of anhydrous potassium carbonate were added and the solution cooled at 0° C.

0.7 g (2.3 mmol) of the compound of Description 3, dissolved in 25 ml of dry DMF, were added dropwise and the solution was kept at 0°-5° C. for 1 hour and at room temperature overnight.

The reaction mixture was evaporated in-vacuo to dryness and the residue was dissolved in EtOAc and washed twice with H₂O. The organic layer was separated, dried over Na₂SO₄, filtered and evaporated in-vacuo to dryness.

The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% NH₄OH to afford 0.1 g of the crude product which was triturated with i-Pr₂O to yield 0.08 g of the title compound.

C₂₆H₂₂N₂O₄M.P.=187-190° C. M.W.=426.48I.R. (KBr): 3220; 1750; 1660; 1620 cm⁻¹. 300 MHz ¹H-NMR (CDCl₃): δ: 8.13-8.08 (m, 3H); 7.80 (s, 1H); 7.55-7.38 (m, 9H); 7.21 (dd, 1H); 7.02 (d broad, H); 5.88 (d, 1H); 3.97 (s, 3H); 3.80 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 426 (M+.); 367; 262; 234; 191; 77.

EXAMPLE 8 (R,S)-N-[α-(methoxycarbonyl)benzyl]-7-hydroxy-2-phenylquinoline-4-carboxamide

Prepared as Ex. 5 from 2.1 g (5.3 mmol) of the compound of Description 4, 1.08, (5.3 mmol) of (D,L) methyl phenylglicinate hydrochloride, 1.5 ml (10.7 mmol) of TEA, 1.7 g (12.5 mmol) of HOBT and 1.2 g (5.8 mmol) of DCC in 70 ml of dry THF and 30 ml of CH₃CN.

The work-up of the reaction mixture was carried out in the same manner as described in Ex. 5. The crude product obtained was triturated with i-Pr₂O and then recrystallized twice from i-PrOH to yield 0.06 g of the title compound.

C₂₅H₂₀N₂O₄M.P.=256-257° C. M.W.=412.45I.R. (KBr): 3270; 1750; 1650; 1620 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 10.30 (s broad, 1H); 9.64 (d, 1H); 8.22 (d, 2H); 8.04 (d, 1H); 7.85 (s, 1H); 7.60-7.34 (m, 9H); 7.21 (dd, 1H); 5.74 (d, 1H); 3.71 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 412 (M+.); 353; 248; 220; 77.

EXAMPLE 9 (R,S)-N-[α-(carboxy)benzyl]-7-methoxy-2-phenylquinoline-4-carboxamide hydrochloride

0.18 g (0.4 mmol) of the product of Ex. 7 were dissolved in 10 ml of 10% HCl and 5 ml of dioxane. The reaction mixture was refluxed and stirred for 3 hours, then evaporated in-vacuo to dryness.

The crude product was triturated with warm EtOAc (containing a few drops of EtOH) to yield 0.16 g of the title compound.

C₂₅H₂₀N₂O₄.HCl M.P.=228-230° C. M.W.=448.91I.R. (KBr): 3180; 1735; 1655; 1630 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.6 (d, 1H); 8.26 (dd, 2H); 8.14 (d, 1H); 7.98 (s, 1H); 7.63-7.52 (m, 6H); 7.46-7.36 (m, 3H); 7.33 (dd, 1H); 5.66 (d, 1H); 3.98 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 412 (M+.); 368; 262; 234; 191; 77.

EXAMPLE 10 (R,S)-N-[α-(methylaminocarbonyl)benzyl]-2-phenylquinoline-4-carboxamide

0.45 g (1.1 mmol) of the product of Ex. 4 were dissolved in 40 ml of 33% MeNH₂/EtOH; a catalitic amount of NaCN was added and the reaction mixture was heated at 70° C. for 1 hour in a parr apparatus. The internal pressure rised to 40 psi. The solution was evaporated in-vacuo to dryness and the residue was triturated with water, filtered, dried and recrystallized from a mixture of i-PrOH (50 ml) and EtOH (30 ml) to yield 0.2 g of the title compound.

C₂₅H₂₁N₃O₂M.P.=261-263° C. M.W.=395.47Elemental analysis: Calcd. C, 75.93; H, 5.35; N, 10.63.Found C, 75.65; H, 5.34; N, 10.55.I.R. (KBr): 3300; 3270; 1660; 1635 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.48 (d, 1H); 8.33-8.25 (m, 3H); 8.18-8.10 (m, 3H); 7.80 (ddd, 1H); 7.68-7.50 (m, 6H); 7.40-7.28 (m, 3H); 5.75 (d, 1H); 2.63 (d, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 395 (M+.); 337; 232; 204; 77.

EXAMPLE 11 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-thienyl)quinoline-4-carboxamide

Prepared as Ex. 5 from 2.0 g (7.3 mmol) of 2-(2-thienyl)quinoline-4-carboxylic acid, 1.7 g (8.4 mmol) of (D,L) methyl phenylglicinate hydrochloride, 1.1 ml (10 mmol) of N-methylmorpholine, 2.1 g (15.5 mmol) of HOBT and 1.85 g (9.0 mmol) of DCC in 70 ml of dry THF, 30 ml of CH₃CN and 10 ml of CH₂Cl₂.

The work-up of the reaction mixture was carried out in the same manner as described in Ex. 5. The crude product obtained was crystallized from EtOAc and then recrystallized from abs. EtOH to yield 0.9 g of the title compound.

C₂₃H₁₈N₂O₃S M.P.=178-180° C. M.W.=402.47Elemental analysis: Calcd. C, 68.64; H, 4.51; N, 6.96.Found C, 67.50; H, 4.99; N, 7.43.I.R. (KBr): 3300; 1745; 1645 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.70 (d, 1H); 8.12 (d, 1H); 8.08 (s, 1H); 8.04 (d, 1H); 8.02 (d, 1H); 7.19 (t, 1H); 7.76 (d, 1H); 7.62 (t, 1H); 7.53 (d, 2H); 7.46-7.37 (m, 3H); 7.3 (dd, 1H); 5.68 (d, 1H); 3.68 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 402 (M+.); 343; 238; 210; 77.

EXAMPLE 12 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(2-furyl)quinoline-4-carboxamide

Prepared as Ex. 1 from 7.2 g (35.5 mmol) of (D,L) methyl phenylglicinate hydrochloride, 12.4 ml (88.8 mmol) of TEA and 9.1 g (35.5 mmol) of crude 2-(2-furyl)quinoline-4-carbonylchloride in 350 ml of a mixture of CH₂Cl₂, CH₃CN and DMF. The work-up of the reaction mixture was carried out in the same manner as described in Ex. 1. The crude product obtained was triturated with MeOH to yield 3.3 g of the title compound.

C₂₃H₁₈N₂O₄M.P.=178-180° C. M.W.=386.405Elemental analysis: Calcd. C, 71.49; H, 4.70; N, 7.25.Found C, 71.67; H, 4.74; N, 7.17.I.R. (KBr): 3300; 1750; 1650 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.72 (d, 1H); 8,12 (d, 1H); 8.06 (d, 1H); 7.96 (dd, 1H); 7.92 (s, 1H); 7.80 (ddd, 1H); 7.62 (ddd, 1H); 7.52 (dd, 2H); 7.45-7.35 (m, 4H); 6.73 (dd, 1H); 5.77 (d, 1H); 3.74 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 386 (M+.); 327; 222; 194; 77.

EXAMPLE 13 (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-(4-pyridyl)quinoline-4-carboxamide

Prepared as Ex. 1 from 3.4 g (16.7 mmol) of (D,L) methyl phenylglicinate hydrochloride, 3.9 ml (27.8 mmol) of TEA and 3.0 g (11.1 mmol) of 2-(4-pyridyl)quinoline-4-carbonylchloride in 100 ml of a mixture of CH₂Cl₂, CH₃CN and DMF. The work-up of the reaction mixture was carried out in the same manner as described in Ex. 1. The crude product obtained was recrystallized three times from EtOAc to yield 1.9 g of the title compound.

C₂₄H₁₉N₃O₃M.P.=172-174° C. M.W.=397.43Elemental analysis: Calcd. C, 72.53; H, 4.82; N, 10.57.Found C, 71.87; H, 4.87; N, 10.44.I.R. (KBr): 3240; 1750; 1670 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.74 (d, 1H); 8.79 (dd, 2H); 8.27-8.17 (m, 5H); 7.89 (ddd, 1H); 7.74 (ddd, 1H); 7.54 (dd, 2H); 7.47-7.38 (m, 3H); 5.8 (d, 1H); 3.75 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 397 (M+.); 338; 233; 205; 77.

EXAMPLE 14 (R,S)-N-[α-(methoxycarbonyl)-2-thienylmethyl]-2-phenylquinoline-4-carboxamide

Prepared as Ex. 1 from 1.94 g (9.4 mmol) of (D,L) methyl thienylglicinate hydrochloride, 2.7 ml (19.5 mmol) of TEA and 2.0 g (7.8 mmol) of 2-phenylquinoline-4-carbonylchloride in 100 ml of a mixture of CH₂Cl₂, CH₃CN and DMF. The work-up of the reaction mixture was carried out in the same manner as described in Ex. 1. The crude product obtained was recrystallized three times from EtOAc to yield 0.66 g of the title compound.

C₂₃H₁₈N₂O₃S M.P.=144-145° C. M.W.=402.47Elemental analysis: Calcd. C, 68.64; H, 4.51; N, 6.96.Found C, 68.81; H, 4.46; N, 6.96.I.R. (KBr): 3295; 1745; 1640 cm⁻¹. 300 MHz ¹H-NMR (CDCl₃): δ 8.25 (dd, 1H); 8.22 (dd, 1H); 8.17 (dd, 2H); 7.95 (s, 1H); 7.78 (ddd, 1H); 7.60 (ddd, 1H); 7.56-7.45 (m, 3H); 7.35 (dd, 1H); 7.20 (d, 1H); 7.05 (dd, 1H); 7.05 (s broad, 1H); 6.22 (d, 1H); 3.9 (s, 3H). MS (EI; source 200° C.; 70 V; 200 mA): 402 (M+.); 343; 232; 204.

EXAMPLE 15 (R,S)-N-[α-(methoxycarbonylmethyl)benzyl]-2-phenylquinoline-4-carboxamide

Prepared as Ex. 5 from 1.39 g (5.60 mmol) of 2-phenylquinoline-4-carboxylic acid, 1.2 g (5.60 mmol) of (R,S) methyl 3-amino-3-phenylpropionate hydrochloride, 0.78 ml (5.60 mmol) of TEA, 1.51 g (11.2 mmol) of HOBT and 2.31 g (11.2 mmol) of DCC in 10 ml of dry THF, 4 ml of CH₃CN and 7 ml of CH₂Cl₂. The work-up of the reaction mixture was carried out in the same manner as described in Ex. 5. The crude product obtained was dissolved in CH₂Cl₂ and left at 0° C. overnight. Some more dicyclohexylurea precipitated and was filtered off.

The solution was evaporated in-vacuo to dryness to obtain 1.4 g of a crude product which was triturated with a mixture of i-Pr₂O/acetone 99:1 to yield 1.2 g of the title compound as a white solid.

C₂₆H₂₂N₂O₃M.P.=156-158° C. M.W.=410.47Elemental analysis: Calcd. C, 76.07; H, 5.40; N, 6.82.Found C, 75.77; H, 5.38; N, 6.94.I.R. (KBr): 3295; 1755; 1645; 1590; 1530 cm¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.40 (d, 1H); 8.29 (dd, 2H); 8.14 (d, 1H); 8.07 (d, 1H); 8.04 (s, 1H); 7.83 (ddd, 1H); 7.66-7.52 (m, 4H); 7.50 (d, 2H); 7.40 (dd, 2H); 7.31 (ddd, 1H); 5.60 (dt, 1H); 3.65 (s, 3H); 3.04-2.89 (m, 2H). MS (EI; source 200° C.; 70 V; 200 mA): 410 (M+.); 337; 233; 205.

TABLE 1

Melting [α]_(D) ²⁰ Ex. Ar R R₁ R₂ R₃ R₄ R₅ * Molecular formula point ° C. c = 0.5, MeOH 1 Ph Me H H H H Ph (R,S) C₂₄H₂₀N₂O 156-157 2 Ph Me H H H H Ph (S) C₂₄H₂₀N₂O 161-162  +25°^(a) 3 Ph Me H H H H Ph (R) C₂₄H₂₀N₂O 158-160  −25°^(a) 4 Ph COOMe H H H H Ph (R,S) C₂₅H₂₀N₂O₃ 170-172 5 Ph COOMe H H H H Ph (S) C₂₅H₂₀N₂O₃ 180-181 +42° 6 Ph COOMe H H H H Ph (R) C₂₅H₂₀N₂O₃ 180-181 −42° 7 Ph COOMe H H 7-OMe H Ph (R,S) C₂₆H₂₂N₂O₄ 187-190 8 Ph COOMe H H 7-OH H Ph (R,S) C₂₅H₂₀N₂O₄ 256-257 9 Ph COOH H H 7-OMe H Ph (R,S) C₂₅H₂₀N₂O₄•HCl 228-230 10 Ph CONHMe H H H H Ph (R,S) C₂₅H₂₁N₃O₂ 261-263 11 Ph COOMe H H H H 2-thienyl (R,S) C₂₃H₁₈N₂O₃S 178-180 12 Ph COOMe H H H H 2-furyl (R,S) C₂₃H₁₈N₂O₄ 178-180 13 Ph COOMe H H H H 4-Py (R,S) C₂₄H₁₉N₃O₃ 172-174 14 2-thienyl COOMe H H H H Ph (R,S) C₂₃H₁₈N₂O₃S 144-145 15 Ph CH₂COOMe H H H H Ph (R,S) C₂₆H₂₂N₂O₃ 156-158 ^(a)solvent DMF

The compounds of the Examples 16-49 of general formula (I) (grouped in the following Table 2) were synthesized starting from the appropriate acyl chlorides of (II) and amines of formula (III) shown in the table and following the synthetic procedure described in Example 1. Acyl chlorides were synthesized starting from the corresponding acid of formula (II) and following Description 1. Reaction yields are calculated on the purified, but unrecrystallized material. Analytical and spectroscopic data of the compounds of the Examples 16-49 are grouped in Table 5.

TABLE 2 Acyl chloride of (II) + (III) → (I) Acyl chloride Stereo Molecular yield m.p. (° C.) [α]_(D) ²⁰ Ex. of (II) (III) (I) chemistry formula M.W. (%) (recryst. solv.) (c = 1, MeOH) 16

(R) C₂₅H₂₂N₂O₃ 398.47 16 120-122(iPr₂O) −18.9(c = 0.5) 17

(R,S)singlediast. C₂₅H₂₂N₂O₂ 382.47 44 204-205(iPrOH/iPr₂O) 18

(R,S) C₂₆H₂₄N₂O₂ 396.49 48 163-165(iPrOH/iPr₂O) 19

(R,S) C₂₉H₃₀N₂O 422.58 30 147-150(hexane) 20

(R,S) C₂₈H₂₄N₂O₃ 436.52 43 186-188(iPrOH/iPr₂O) 21

(R,S) C₃₁H₃₄N₂O 450.63 24 131-134(hexane/iPr₂O) 22

(S) C₂₆H₂₄N₂O 380.49 58 153-155(iPr₂O) −36.0 23

(R) C₂₆H₂₄N₂O 380.49 78 155-156(iPr₂O) +35.9 24

(R,S) C₂₆H₂₂N₂O₄ 426.48 55 124-125(toluene) 25

(R,S) C₃₁H₂₆N₂O 442.57 49 198-200(toluene) 26

(R,S) C₂₅H₁₉FN₂O₃ 414.44 75 146-147(toluene) 27

(R,S) C₂₅H₂₀Cl₂N₂O 435.36 44 193-194(toluene) 28

(R,S) C₂₄H₂₀N₂O₂ 368.43 24 117-119(toluene) 29

(R,S) C₂₅H₂₂N₂O 366.47 80 141-143(toluene) 30

(R,S) C₂₆H₂₂N₂O₃ 410.48 60 180-181(toluene/iPr₂O) 31

(R,S) C₂₆H₂₄N₂O 380.49 55 156-158(toluene/hexane) 32

(R,S) C₂₅H₁₉ClN₂O₃ 430.90 48 180-183(toluene) 33

(R,S) C₂₆H₂₂N₂O₃ 410.48 48 179-181(toluene) 34

(R,S) C₂₅H₂₂N₂O₂ 382.47 42 144-145(toluene) 35

(R,S) C₂₅H₁₉ClN₂O₃ 430.90 46 197-199(toluene) 36

(R,S) C₂₇H₂₄N₂O₃ 424.50 52 156-157(toluene/hexane) 37

(R,S) C₂₆H₂₄N₂O 380.49 50 149-150(toluene) 38

(R,S) C₂₇H₂₆N₂O 394.52 53 158-159(Et₂O/iPr₂O) 39

(R,S) C₃₃H₂₅N₃O₃ 511.58 16 201-202(toluene) 40

(R,S) C₂₈H₂₈N₂O 408.55 71 149-151(toluene/hexane) 41

(S) C₂₆H₂₂Br₂N₂O 538.30 24 230-231(Et₂O/iPr₂O) −49.8(c = 0.2) 42

(S) C₂₆H₂₃BrN₂O 459.40 39 179-180(hexane/iPrOH) −60.5 43

(R,S) C₂₆H₂₂N₂O₄ 426.48 45 209-211(Me₂CO) 44

(R,S) C₂₇H₂₀N₂O₄ 436.47 65 240-241(EtOAc) 45

(R,S) C₃₀H₂₄N₂O 428.53 47 194-196(EtOAc) 46

(R,S) C₂₄H₁₇F₃N₂O 406.41 45 180-181(toluene) 47

(S) C₂₆H₂₄N₂O₂ 396.49 58 132-134(Me₂CO) −45  (c = 0.5) 48

(S) C₂₇H₂₆N₂O 394.52 53 118-120(hexane) −42  (c = 0.5) 49

(R,S) C₂₅H₂₁ClN₂O 400.91 40 177-178(toluene)

The compounds of the Examples 50-88 of general formula (I) (grouped in the following Table 3) were synthesized starting from the appropriate reagents (II) and (III) shown in the table and following the synthetic procedure described in Example 5. Reaction yields are calculated on the purified, but unrecrystallized material. Analytical and spectroscopic data of the compounds of the Examples 50-88 are grouped in Table 5.

TABLE 3

Stereo Molecular yield m.p. (° C.) [a]_(D) ²⁰ Ex. (II) (III) (I) chemistry formula M.W. (%) (recryst. solv.) (c = 1, MeOH) 50

(R, S) C₂₆H₂₂N₂O₃ 410.48 46 128-129(iPrOH) 51

(R, S) C₂₃H₁₈N₂O₃S 402.47 88 169-171(iPrOH) 52

(R, S) C₂₇H₂₂N₂O₃ 422.49 41 217-219(EtOH abs.) 53

(R, S) C₂₃H₁₉N₃O₃ 385.42 44 181-182(iPrOH) 54

(R, S) C₂₂H₁₇N₃O₃S 403.45 50 209-211(iPrOH) 55

(R, S) C₂₅H₂₀N₂O 364.45 95 183-184(iPrOH) 56

(R, S) C₂₇H₂₆N₂O 394.52 77 155-156(iPrOH/iPr₂O) 57

(R, S) C₂₆H₂₂N₂O₃ 410.48 83 172-174(iPrOH) 58

(R, S) C₃₀H₃₂N₂O 436.60 91 121-128(iPr₂O) 59

(R, S) C₂₆H₂₂N₂O₃ 410.48 79 180-182(iPrOH) 60

(R, S) C₂₆H₂₂N₂O₄ 426.48 62 182-183(iPrOH) 61

— C₂₇H₂₄N₂O 392.51 82 164-165(iPrOH) 62

(R, S) C₂₅H₂₀N₂O₄ 412.45 50 226-227(iPrOH) 63

(R, S) C₂₆H₂₀N₂O₅ 440.46 70 186-187(iPrOH) 64

— C₂₅H₂₂N₂O 366.47 75 173-174(iPrOH) 65

(R, S) C₂₆H₂₄N₂O 380.49 90 160-162(iPrOH) 66

(R, S) C₂₃H₁₉N₃O₃ 385.42 10 202-204(iPr₂O) 67

(R, S) C₂₅H₁₈Cl₂N₂O₃ 465.34 59 164-165(iPrOH) 68

(R) C₂₄H₂₁N₃O 367.45 49 139-141(iPrOH/iPr₂O)  −6.9(c = 0.5) 69

(S) C₂₅H₂₃N₃O 381.48 78 153-155(iPrOH/iPr₂O) −68.0(c = 0.5) 70

(S) C₂₅H₂₁ClN₂O 400.91 58 137-139(toluene/hexane) −40.5(c = 0.5) 71

(S) C₂₅H₂₁BrN₂O 445.37 20 119-122(toluene/hexane) −41.4(c = 0.5) 72

(R, S) C₂₆H₂₄N₂O 380.49 59 165-166(iPrOH) 73

(S) C₂₅H₂₂N₂O 366.46 77 140-141(iPrOH) −26.7 74

(R) C₂₅H₂₂N₂O 366.46 51 151-152(iPrOH) +26.6 75

(R, S) C₂₅H₁₉FN₂O₃ 414.44 44 174-176(toluene/EtOAc) 76

(R, S) C₂₅H₂₆N₂O₃ 402.50 53 151-153(EtOAc) 77

(R, S) C₂₅H₁₉ClN₂O₃ 430.90 68 161-163(toluene/hexane) 78

(R, S) C₂₅H₁₉ClN₂O₃ 430.90 43 175-178(toluene/hexane) 79

(R, S) C₂₅H₂₂N₂O₂ 382.47 47 168-169(toluene) 80

(R, S) C₂₇H₂₂N₂O₅ 454.49 16 193-194(toluene) 81

(R, S) C₂₅H₂₀N₂O₄ 412.40 32 178-180(toluene) 82

(R, S) C₂₅H₁₈Cl₂N₂O₃ 465.34 61 142-143(iPrOH) 83

(R) C₂₅H₂₀N₂O₄• HCl 448.88 50 140 dec.(Me₂CO)  −7   84

— C₂₉H₂₂N₂O 414.51 42 182-184(EtOAc) 85

(S) C₂₅H₂₂N₂O₂ 382.47 66 122-125(iPr₂O) −28.4(c = 0.5) 86

(R) C₂₅H₂₂N₂O₂ 382.47 66 122-125(hexane/EtOAc) +27.2(c = 0.5) 87

(R) C₂₅H₂₀N₂O₄ 412.45 70 125-127(iPr₂O) −50  (c = 0.5) 88

(R) C₂₆H₂₅N₃O 395.51 26 133-135(iPr₂O/iPrOH) −11.2(c = 0.5) (a) the phthalimido protecting group was removed by refluxing for 4 h with hydrate hydrazine in 95% EtOH/1,2 dichloroethane, 9:1 respectively and then adding 37% HCl (up to pH = 1) and refluxing an additional hour.

The compounds of the Examples 89-92 of general formula (I) (grouped in the following Table 4) were synthesized starting from other compounds of formula (I) (i.e. compounds of formula Ic) and following the synthetic procedures described in Example 10 (for compounds of the Examples 89, 90 and 91) and in Example 9 (for compound of the Example 92). Reaction yields are calculated on the purified, but unrecrystallized material. Analytical and spectroscopic data of the compounds of the Examples 89-92 are grouped in Table 5.

TABLE 4 (Ic) → (I) Stereo m.p. (° C.) [α]_(D) ²⁰ chem- Molecular yield (recryst. (c = Ex. (Ic) (I) istry formula M.W. (%) solv.) 1, MeOH) 89

(R,S) C₂₆H₂₃N₃O₂ 409.49 22 219-221(iPrOH/EtOH) 90

(R,S) C₂₄H₁₉N₃O₂ 381.43 95 237-238(iPrOH/EtOH) 91

(R,S) C₂₈H₂₅N₃O₂ 435.53 69 199-200(iPrOH) 92

(R) C₂₄H₁₈N₂O₃.HCl 418.88 94 203-205(acetone) −40.0(c = 0.5)

TABLE 5 Analytical and spectroscopic data of compounds of Examples 16–92 MS(EI; source 200° C.; Ex. Elemental analysis IR(KBr); cm⁻¹ 70eV; 200μA) 300MHz ¹H NMR(DMSO), 303K 16 3240; 1750; 398(M+.); 232; 204 9.40(d, 1H); 8.30(d, 2H); 8.18(d, 1H); 8.13(d, 1H); 1640; 1595; 8.10(s, 1H); 7.83(dd, 1H); 7.66(dd, 1H); 7.63–7.51(m, 3H); 1545 5.87(s br, 1H); 5.70(m, 2H); 5.12(d, 1H); 3.80(s, 3H); 2.92–2.60(m, 4H). 17 Calcd. C, 78.51; H, 5.80; N, 7.32 3400; 3200; 337(M-C₂H₄OH)+; 9.20(d, 1H); 8.31(d, 2H); 8.14(d, 1H); 8.08(s, 1H); Found C, 78.27; H, 5.83; N, 7.24 1640; 1595; 232; 204 8.04(d, 1H); 7.82(dd, 1H); 7.64–7.51(m, 4H); 7.47(d, 2H); 1532 7.37(dd, 2H); 7.27(dd, 1H); 5.10(dd, 1H); 4.81(d, 1H); 4.13(dq, 1H); 1.18(d, 3H). 18 Calcd. C, 78.76; H, 6.10; N, 7.07 3260; 3220; 396(M+.); 367; 262; 219 9.24(d, 1H); 8.07(d, 1H); 7.97(dd, 2H); Found C, 78.60; H, 6.08; N, 7.00 1632; 1550* 7.76–7.70(m, 1H); 7.62–7.51(m, 5H); 7.46(d, 2H); 7.39(dd, 2H); 7.29(dd, 1H); 5.10(dt, 1H); 3.52(s, 3H); 1.82(dq, 2H); 1.00(t, 3H). 19 Calcd. C, 82.43; H, 7.16; N, 6.63 3240; 1630; 423(MH+)^(•) (353K): 8.89(d br, 1H); 8.00(d, 1H); 7.70(dd, 1H); Found C, 82.31; H, 7.20; N, 6.58 1540 7.60–7.42(m, 9H); 7.36(dd, 2H); 7.28(dd, 1H); 5.13(dt, 1H); 2.66(m, 2H); 1.90(ddq, 2H); 1.30(m, 2H); 1.00(t, 3H); 0.95(m, 2H); 0.57(t br, 3H). 20 Calcd. C, 77.04; H, 5.54; N, 6.42 3290; 1760; 436(M+.); 377; 272; 271 (353K): 9.50(d, 1H); 8.08(d, 1H); 7.88(d, 1H); Found C, 76.81; H, 5.54; N, 6.35 1645; 1590; 7.80–7.72(m, 2H); 7.60(dd, 1H); 7.52(dd, 2H); 1532 7.47–7.30(m, 6H); 5.90(d, 1H); 2.60(t, 2H); 2.57(t, 2H); 2.26–2.06(m, 2H). 21 Calcd. C, 82.63; H, 7.61; N, 6.22 3270; 1635; 450(M+.); 421; 316 (373K): 8.71(d br, 1H); 7.99(d, 1H); 7.70(m, 2H); Found C, 82.84; H, 7.64; N, 6.16 1550* 7.52–7.42(m, 8H); 7.37(dd, 2H); 7.27(dd, 1H); 5.12(dt, 1H); 2.67(dd, 2H); 1.91(ddq, 2H); 1.36–1.26(m, 2H); 1.12–1.02(m, 2H); 1.00(t, 3H); 1.00–0.90(m, 4H); 0.76(t, 3H). 22 Calcd. C, 82.07; H, 6.36; N, 7.36 3260; 1630; 380(M+.); 351; 246; 218 (353K): 8.90(d br, 1H); 8.01(d, 1H); 7.72(dd, 1H); Found C, 81.95; H, 6.33; N, 7.30 1535 7.65(d br, 1H); 7.60–7.49(m, 6H); 7.46(d, 2H); 7.38(dd, 2H); 7.24(dd, 1H); 5.12(dt, 1H); 2.30(s, 3H); 1.98–1.78(m, 2H); 0.99(t, 3H). 23 Calcd. C, 82.07; H, 6.36; N, 7.36 3260; 1630; 380(M+.); 351; 246; 218 (353K): 8.90(d br, 1H); 8.01(d, 1H); 7.72(dd, 1H); Found C, 81.80; H, 6.37; N, 7.30 1535 7.65(d br, 1H); 7.60–7.49(m, 6H); 7.46(d, 2H); 7.38(dd, 2H); 7.24(dd, 1H); 5.12(dt, 1H); 2.30(s, 3H); 1.98–1.78(m, 2H); 0.99(t, 3H). 24 Calcd. C, 73.22; H, 5.20; N, 6.57 3282; 1750; 426(M+.); 367; 277 9.65(d, 1H); 8.18(d, 1H); 8.11(d, 1H); 7.96(s, 1H); Found C, 72.88; H, 5.25; N, 6.44 1640; 1530 7.83(dd, 1H); 7.81(dd, 1H); 7.66(dd, 1H); 7.54–7.46(m, 3H); 7.44–7.33(m, 3H); 7.22(d, 1H); 7.13(dd, 1H); 5.80(d, 1H); 3.87(s, 1H); 3.71(s, 3H). 25 Calcd. C, 84.13; H, 5.92; N, 6.33 3250; 1630; 442(M+.); 413; 308; 280 8.86(d, 1H); 8.13(d, 1H); 7.83(dd, 1H); Found C, 82.28; H, 5.86; N, 6.19 1545 7.71–7.59(m, 2H); 7.31–7.14(m, 12H); 7.04(d br, 2H); 4.75(dt, 1H); 1.58–1.42(m, 2H); 0.63(t br, 3H). 26 Calcd. C, 72.45; H, 4.62; N, 6.76 3320; 1745; 414(M+.); 355; 250; 222 9.70(d, 1H); 8.21(d, 1H); 8.16(d, 1H); 8.07(dd, 1H); Found C, 72.19; H, 4.66; N, 6.69 1650; 1595 7.90(d, 1H); 7.86(dd, 1H); 7.72(dd, 1H); 7.64–7.55(m, 1H); 7.51(dd, 1H); 7.45–7.34(m, 4H); 5.80(d, 1H); 3.75(s, 3H). 27 Calcd. C, 69.03; H, 4.62; N, 6.44 3250; 1650; 434(M+.); 405; 232; 204 9.50(d, 1H); 8.31(d, 2H); 8.15(d, 1H); 8.10(s, 1H); Found C, 68.97; H, 4.63; N, 6.43 1585; 1550 8.00(d, 1H); 7.81(dd, 1H); 7.72(d, 1H); 7.66(d, 1H); 7.64–7.52(m, 4H); 7.46(dd, 1H); 4.11(dt, 1H); 1.83(dq, 2H); 0.98(t, 3H). 28 Calcd. C, 78.24; H, 5.47; N, 7.60 3260; 1645; 368(M+.); 337; 232; 204 9.22(d, 1H); 8.33(d, 2H); 8.18(s, 1H); 8.13(d, 2H); Found C, 78.49; H, 5.58; N, 7.41 1590; 1550 7.81(dd, 1H); 7.64–7.51(m, 4H); 7.46(d, 2H); 7.37(dd, 2H); 7.28(dd, 1H); 5.21(dt, 1H); 5.05(t, 1H); 3.71(dd, 2H). 29 Calcd. C, 81.93; H, 6.05; N, 7.64 3260; 1650; 366(M+.); 337; 232; 204 9.24(d, 1H); 8.30(d, 2H); 8.14(d, 1H); 8.09(s, 1H); Found C, 81.79; H, 6.06; N, 7.62 1595; 1550 8.02(d, 1H); 7.82(dd, 1H); 7.63–7.51(m, 4H); 7.46(d, 2H); 7.38(dd, 2H); 7.24(dd, 1H); 5.14(dt, 1H); 1.95–1.78(m, 2H); 0.98(t, 3H). 30 Calcd. C, 76.08; H, 5.40; N, 6.83 3260; 1755; 410(M+.); 351; 261; 9.70(d, 1H); 8.02(d, 1H); 7.76(dd, 1H); Found C, 75.88; H, 5.37; N, 7.08 1735; 1640; 246; 217 7.70–7.47(m, 9H); 7.47–7.34(m, 3H); 6.82(d, 1H); 3.75(s, 3H); 1580; 1530 2.32(s br, 3H). 31 Calcd. C, 82.08; H, 6.36; N, 7.36 3220; 1630; 380(M+.); 351; 246; 217 (353K): 9.00(d, 1H); 8.01(d, 1H); 7.37(dd, 1H); Found C, 81.82; H, 6.34; N, 7.33 1550 7.60–7.48(m, 7H); 7.45(d, 2H); 7.38(dd, 2H); 7.28(dd, 1H); 5.10(dt, 1H); 2.28(s, 3H); 2.00–1.80(m, 2H); 1.00(t, 3H). 32 Calcd. C, 69.69; H, 4.45; N, 6.50 3270; 1750; 430(M+.); 371; 266; 238; 9.78(d, 1H); 8.29(d, 2H); 8.24(d, 1H); 8.19(d, 1H); Found C, 69.58; H, 4.49; N, 6.49 1670; 1595; 203 8.16(s, 1H); 7.73(dd, 1H); 7.61–7.49(m, 5H); 1520 7.47–7.36(m, 3H); 5.80(d, 1H); 3.79(s, 3H). 33 Calcd. C, 76.49; H, 5.40; N, 6.82 3240; 1750; 410(M+.); 351; 246; 218 9.70(d, 1H); 8.26(d, 2H); 8.08(s, 1H); 8.03(d, 1H); Found C, 76.74; H, 5.40; N, 6.88 1665; 1590; 7.96(s, 1H); 7.68(dd, 1H); 7.60–7.50(m, 5H); 1510; 1500 7.48–7.36(m, 3H); 5.80(d, 1H); 3.79(s, 3H); 2.50(s, 3H). 34 Calcd. C, 78.51; H, 5.79; N, 7.32, 3220; 1740; 382(M+.); 337; 232; 204 9.35(d, 1H); 8.32(d, 2H); 8.14(d, 1H); 8.11(d, 1H); Found C, 78.78; H, 5.78; N, 7.23 1695; 1535 8.10(s, 1H); 7.84(dd, 1H); 7.64(dd, 1H); 7.61–7.54(m, 3H); 7.50(d, 2H); 7.40(dd, 2H); 7.30(dd, 1H); 5.41(dt, 1H); 3.73–3.60(m, 2H); 3.36(s, 3H). 35 Calcd. C, 69.69; H, 4.45; N, 6.50 3240; 1750; 430(M+.); 371; 266; 9.80(d, 1H); 8.29(d, 2H); 8.27(d, 1H); 8.21(s, 1H); Found C, 70.27; H, 4.46; N, 6.45 1670; 1590; 238; 203 8.16(d, 1H); 7.86(dd, 1H); 7.61–7.51(m, 5H); 1550; 1500 7.48–7.38(m, 3H); 5.80(d, 1H); 3.75(s, 3H). 36 Calcd. C, 76.40; H, 5.70; N, 6.60 3240; 1760; 425(MH+)^(•) (353K): 9.52(d, 1H); 8.01(d, 1H); 7.89(s br, 1H); Found C, 76.44; H, 5.72; N, 6.62 1640; 1540 7.74(dd, 1H); 7.60(dd, 1H); 7.54–7.48(m, 7H); 7.44–7.33(m, 3H); 4.88(d, 1H); 3.78(s, 3H); 2.91–2.68(m, 2H); 0.91(t, 3H). 37 Calcd. C, 82.08; H, 6.36; N, 7.36 3300; 1635; 380(M+.); 337; 232; 204 9.28(d, 1H); 8.14(d, 1H); 8.07(s, 1H); 8.01(d, 1H); Found C, 82.21; H, 6.39; N, 7.34 1590; 1545 7.82(dd, 1H); 7.64–7.51(m, 4H); 7.46(d, 2H); 7.39(dd, 2H); 7.28(dd, 1H); 5.15(dt, 1H); 1.94–1.69(m, 2H); 1.54–1.29(m, 2H); 0.95(t, 3H). 38 Calcd. C, 82.20; H, 6.64; N, 7.10 3240; 1640; 395(MH+); CI; gas (353K): 8.91(d, 1H); 8.00(d, 1H); 7.71(dd, 1H); Found C, 82.34; H, 6.64; N, 7.07 1550 reagent methane; P 5000 7.68–7.48(m, 7H); 7.45(d, 2H); 7.39(dd, 2H); 7.29(dd, 1H); mTorr; source 150° C. 5.11(dt, 1H); 2.78–2.62(m, 2H); 2.00–1.80(m, 2H); 1.00(t, 3H); 0.90(t br, 3H). 39 Calcd. C, 77.48; H, 4.93; N, 8.21 3330; 1790; 511(M+.); 482; 377; (353K): 8.90(d, 1H); 8.20(d, 1H); 7.94(dd, 1H); Found C, 77.25; H, 4.99; N, 8.07 1720; 1665; 349; 321 7.88–6.90(m, 5H); 7.74(d, 1H); 7.69(dd, 1H); 1530 7.48–7.42(m, 2H); 7.36–7.31(m, 3H); 7.25–7.20(m, 2H); 7.18–7.10(m, 2H); 4.85(dt, 1H); 1.73(ddq, 1H); 0.82(t, 3H). 40 Calcd. C, 82.32; H, 6.91; N, 6.86 3250; 1635; 408(M+.); 379, 289, (373K): 8.72(d, 1H); 8.00(d, 1H); 7.70(dd, 1H); Found C, 82.02; H, 6.95; N, 6.90 1550 274; 246 7.55–7.42(m, 9H); 7.38(dd, 2H); 7.28(dd, 1H); 5.15(dt, 1H); 2.66(dd, 2H); 1.94(ddq, 2H); 1.33(m, 2H); 1.01(t, 3H); 0.56(t, 3H). 41 Calcd. C, 58.02; H, 4.12; N, 5.20; 3250; 1650; 537/539/541(MH+)^(•) (353K): 8.95(d, 1H); 7.96(d, 1H); 7.83(dd, 1H); Br, 29.69 1540 7.76(d, 1H); 7.71(d, 2H); 7.55(d, 2H); 7.45(dd, 2H); Found C, 58.14; H, 4.18; N, 5.22; 7.39(dd, 2H); 7.30(dd, 1H); 5.10(dt, 1H); 2.92(s, 3H); Br, 29.44 2.30(s, 3H); 1.88(ddq, 2H); 1.01(t, 3H). 42 Calcd. C, 67.98; H, 5.04; N, 6.10; 3260; 1640; 459/461(MH+)^(•) (353K): 8.94(d br, 1H); 7.96(d, 1H); 7.81(dd, 1H); Br, 17.39 1540 7.76(d, 1H); 7.60–7.49(m, 4H); 7.45(d, 2H); 7.40(dd, 2H); Found C, 68.04; H, 5.02; N, 6.05; 7.30(dd, 1H); 5.10(dt, 1H); 2.30(s, 3H); 1.89(ddq, 2H); Br, 17.26 1.01(t, 3H). 43 Calcd. C, 73.22; H, 5.20; N, 6.57 3200; 1750; 426(M+.); 367; 262; 234 9.70(d, 1H); 8.24(d, 2H); 8.08(s, 1H); 8.05(d, 1H); Found C, 73.41; H, 5.39; N, 6.61 1665; 1620; 7.61(d, 1H); 7.58–7.35(m, 9H); 5.80(d, 1H); 3.89(s, 3H); 1520 3.74(s, 3H). 44 Calcd. C, 74.30; H, 4.62; N, 6.42 3200; 1750; 436(M+.); 337; 272; 244 9.80(d, 1H); 8.18(d, 1H); 8.11(d, 1H); 8.09(s, 1H); Found C, 74.28; H, 4.61; N, 6.41 1660; 1590; 7.90(s, 1H); 7.87(dd, 1H); 7.80(d, 1H); 7.77(d, 1H); 1550; 1525; 7.67(dd, 1H); 7.54(d, 2H); 7.47–7.31(m, 5H); 5.80(d, 1H); 1500 3.78(s, 3H). 45 Calcd. C, 84.08; H, 5.65; N, 6.54 3320; 1635; 337(M-C₇H₇)+; 232; 9.32(ABXY, 1H); 8.22(d, 2H); 8.09(d, 1H); Found C, 84.13; H, 5.65; N, 6.51 1590; 1530 204; 91 7.78(dd, 1H); 7.77(s, 1H); 7.64–7.52(m, 6H); 7.50–7.28(m, 9H); 5.53(ABXY, 1H); 3.20(ABXY, 1H); 3.16(ABXY, 1H). 46 Calcd. C, 70.91; H, 4.22; N, 6.89; 3300; 1655; 406(M+.); 386; 232; 204 10.15(d, 1H); 8.30(dd, 2H); 8.18(d, 1H); 8.10(s, 1H); F, 14.02 1590; 1540; 7.98(d, 1H); 7.86(dd, 1H); 7.75–7.42(m, 9H); Found C, 70.86; H, 4.17; N, 6.92; 1500 6.21(m, 1H). F, 13.88 47 Calcd. C, 78.74; H, 6.10; N, 7.06 3250; 1635; 396(M+.); 367; 262; 219 9.24(d, 1H); 8.07(d, 1H); 7.97(dd, 2H); Found C, 78.72; H, 6.10; N, 7.01 1550; 1500 7.76–7.70(m, 1H); 7.62–7.51(m, 5H); 7.46(d, 2H); 7.39(dd, 2H); 7.29(dd, 1H); 5.10(dt, 1H); 3.52(s, 3H); 1.82(dq, 2H); 1.00(t, 3H). 48 Calcd. C, 82.18; H, 6.64; N, 7.10 3250; 1630; 394(M+.); 365; 275; 260 (353K): 8.90(d br, 1H); 8.00(d, 1H); 7.70(dd, 1H); Found C, 81.93; H, 6.64; N, 7.05 1540; 1500 7.56–7.42(m, 9H); 7.38(dd, 2H); 7.29(dd, 1H); 5.13(dt, 1H); 2.72(m, 2H); 1.90(ddq, 2H); 1.00(t, 3H); 0.90(t br, 3H). 49 Calcd. C, 74.90; H, 5.28; N, 6.99; 3270; 1645; 400(M+.); 371; 232; 204 9.20(d, 1H); 8.32(d, 2H); 8.08(dd, 2H); 8.06(s, 1H); Found C, 74.67; H, 5.33; N, 7.03; 1590; 1550; 7.82(t, 1H); 7.65–7.40(m, 8H); 5.00(dt, 1H); 1495; 770 1.93–1.73(m, 2H); 0.98(t, 3H). 50 Calcd. C, 76.08; H, 5.40; N, 6.82 1750; 1640; 411(MH+); 232; 204^(•) 8.32(d, 2H); 8.16(d, 1H); 8.10(s, 1H); 7.88(dd, 1H); Found C, 76.16; H, 5.42; N, 6.84 1595; 1550 7.71(dd, 1H); 7.60–7.42(m, 9H); 3.86(s, 3H); 2.56(s, 3H). 51 Calcd. C, 68.64; H, 4.51; N, 6.96 3290; 1740; 402(M+.); 343; 238; 210 9.72(d, 1H); 8.47(dd, 1H); 8.15(d, 1H); 8.07(d, 1H); Found C, 68.52; H, 4.53; N, 6.94 1640; 1590; 8.05(s, 1H); 7.96(dd, 1H); 7.81(dd, 1H); 7.71(dd, 1H); 1530 7.62(dd, 1H); 7.53(d, 2H); 7.46–7.36(m, 3H); 5.78(d, 1H); 3.78(s, 3H). 52 Calcd. C, 76.76; H, 5.25; N, 6.63 3250; 1750; 422(M+.); 258; 230 9.70(d, 1H); 8.45(dd, 1H); 8.18(d, 1H); Found C, 76.39; H, 5.25; N, 6.55 1660; 1590; 7.80–7.38(m, 11H); 5.83(d, 1H); 3.79(s, 3H); 3.20–2.80(s br, 4H). 1520 53 Calcd. C, 71.68; H, 4.97; N, 10.90 3410; 3250; 385(M+.); 221; 193 11.68(s br, 1H); 9.71(d, 1H); 8.17(d, 1H); 7.99(d, 1H); Found C, 71.39; H, 4.99; N, 10.81 1740; 1678; 7.86(s, 1H); 7.66(dd, 1H); 7.58–7.35(m, 6H); 7.00(s 1600* br, 2H); 6.22(s br, 1H); 5.75(d, 1H); 3.73(s, 3H). 54 Calcd. C, 65.50; H, 4.25; N, 10.42 3300; 1755; 344(M-COOCH₃)+; 9.82(d, 1H); 8.28(s, 1H); 8.19(d, 1H); 8.14(d, 1H); Found C, 65.48; H, 4.22; N, 10.38 1645; 1585; 239; 211 8.10(d, 1H); 8.00(d, 1H); 7.88(dd, 1H); 7.73(dd, 1H); 1530 7.53(d, 2H); 7.47–7.36(m, 3H); 5.80(d, 1H); 3.78(s, 3H). 55 Calcd. C, 82.39; H, 5.53; N, 7.69 3240; 1640; 365(MH)+^(•) 9.20(d, 1H); 8.31(d, 2H); 8.27(d, 1H); 8.16(s, 1H); Found C, 82.31; H, 5.52; N, 7.65 1590; 1545 8.14(d, 1H); 7.85(dd, 1H); 7.68(dd, 1H); 7.62–7.46(m, 4H); 7.32–7.23(m, 3H); 5.69(dt, 1H); 3.08–2.85(m, 2H); 2.64–2.52(m, 1H); 2.10–1.96(m, 1H). 56 Calcd. C, 82.20; H, 6.64; N, 7.10 3270; 1640; 394(M+.); 337; 232; 204 9.12(d, 1H); 8.30(d, 2H); 8.14(d, 1H); 8.07(s, 1H); Found C, 82.29; H, 6.66; N, 7.05 1590; 1540 8.02(d, 1H); 7.82(dd, 1H); 7.64–7.52(m, 4H); 7.46(d, 2H); 7.39(dd, 2H); 7.28(dd, 1H); 5.13(dt, 1H); 1.96–1.71(m, 2H); 1.48–1.27(m, 4H); 0.9(t, 3H). 57 Calcd. C, 76.08; H, 5.40; N, 6.82 3300; 1752; 410(M+.); 351; 246; 9.74(d, 1H); 8.20(d, 2H); 8.18(d, 1H); 8.12(d, 1H); Found C, 75.92; H, 5.44; N, 6.77 1642; 1590; 218; 203 8.08(s, 1H); 7.82(dd, 1H); 7.64(dd, 1H); 7.54(d, 2H); 1530 7.47–7.36(m, 5H); 5.8(d, 1H); 3.79(s, 3H); 2.40(s, 3H). 58 Calcd. C, 82.53; H, 7.39; N, 6.42 3260; 1650; 337(M-C₇H₁₅)+; 249; 9.28(d, 1H); 8.29(d, 2H); 8.14(d, 1H); 8.07(s, 1H); Found C, 82.59; H, 7.45; N, 6.39 1590; 1550; 232; 204 8.02(d, 1H); 7.82(dd, 1H); 7.64–7.52(m, 4H); 7.46(d, 2H); 1540 7.38(dd, 2H); 7.28(dd, 1H); 5.14(dt, 1H); 1.98–1.71(m, 2H); 1.30–1.20(m, 10H); 0.86(t br, 3H). 59 Calcd. C, 76.08; H, 5.40; N, 6.82 3400–3100; 410(M+.); 261; 218 9.70(d, 1H); 8.22(d, 1H); 8.10(d, 1H); 7.84(dd, 1H); Found C, 76.21; H, 5.40; N, 6.79 1742; 1665; 7.70(dd, 1H); 7.67(s, 1H); 7.56(d, 1H); 7.50(dd, 2H); 1590; 1530 7.45–7.33(m, 5H); 5.80(d, 1H); 3.78(s, 3H); 2.42(s, 3H). 60 Calcd. C, 73.22; H, 5.20; N, 6.57 3300; 1750; 426(M+.); 367; 262; 9.72(d, 1H); 8.25(d, 2H); 8.17(d, 1H); 8.09(d, 1H); Found C, 72.89; H, 5.20; N, 6.48 1645; 1590; 234; 219; 191 8.07(s, 1H); 7.80(dd, 1H); 7.62(dd, 1H); 7.54(dd, 2H); 1520 7.46–7.36(m, 3H); 7.12(d, 2H); 5.80(d, 1H); 3.89(s, 3H); 3.75(s, 3H). 61 Calcd. C, 82.62; H, 6.16; N, 7.14 3230; 1640; 392(M+.); 249; 232, 204 9.00(s, 1H); 8.32(dd, 2H); 8.13(d, 1H); 8.05(s, 1H); Found C, 82.76; H, 6.18; N, 7.19 1590; 1550* 7.93(d, 1H); 7.81(dd, 1H); 7.64–7.52(m, 6H); 7.39(dd, 2H); 7.26(dd, 1H); 2.61–2.50(m, 2H); 2.10–2.00(m, 2H); 2.00–1.75(m, 4H). 62 Calcd. C, 72.80; H, 4.89; N, 6.79 3500–3100; 412(M+.); 353; 248; 220 9.90(s, 1H); 9.70(d, 1H); 8.14(d, 2H): 8.14(d, 1H); Found C, 72.86; H, 4.91; N, 6.75 1750; 1670; 8.06(d, 1H); 8.01(s, 1H); 7.78(dd, 1H); 7.60(dd, 1H); 1640; 1590 7.53(dd, 2H); 7.46–7.35(m, 3H); 6.94(d, 2H); 5.80(d, 3H); 3.75(s, 3H). 63 Calcd. C, 70.90; H, 4.58; N, 6.36 3350; 1735; 440(M+.); 381; 276; 248 9.70(d, 1H); 8.17(d, 1H); 8.09(d, 1H); 8.06(s, 1H): Found C, 70.73; H, 4.59; N, 6.35 1655; 1590 7.88(d, 1H); 7.85(dd, 1H); 7.80(dd, 1H); 7.62(dd, 1H); 7.42(dd, 2H); 7.46–7.36(m, 3H); 7.10(d, 2H); 6.13(s, 2H); 5.73(d, 1H); 3.73(s.3H). 64 Calcd. C, 81.94; H, 6.05; N, 7.64 3220; 1640; 366(M+.); 351; 248; 9.01(s br, 1H); 8.34(dd, 2H); 8.15(s, 1H); 8.13(d, 1H); Found C, 82.02; H, 6.07; N, 7.60 1590; 1545 232; 204 8.01(d, 1H); 7.81(dd, 1H); 7.66–7.52(m, 6H); 7.39(dd, 2H); 7.25(dd, 1H). 65 Calcd. C, 82.07; H, 6.36; N, 7.36 3320; 1640; 380(M+.); 351; 232; 204 9.20(d, 1H); 8.29(dd, 2H); 8.14(d, 1H); 8.06(s, 1H); Found C, 82.15; H, 6.36; N, 7.41 1590; 1530 8.03(d, 1H); 7.81(dd, 1H); 7.64–7.50(m, 4H); 7.34(d, 2H); 7.19(d, 2H); 5.00(dt, 1H); 2.30(s, 3H); 1.93–1.73(m, 2H); 0.98(t, 3H). 66 Calcd. C, 71.68; H, 4.97; N, 10.90 3360; 3240; 385(M+.); 326; 221; 193 11.20(s br, 1H); 9.65(d, 1H); 8.05(d, 1H); 7.93(d, 1H); Found C, 70.42; H, 4.99; N, 10.56 1750; 1630; 7.78(s, 1H); 7.70(dd, 1H); 7.67(m, 1H); 1600; 1560 7.55–7.34(m, 6H); 6.87(m, 1H); 6.80(m, 1H); 6.77(d, 1H); 3.75(s, 3H). 67 Calcd. C, 64.53; H, 3.90; N, 6.02; 3200; 1755; 464(M+.); 405; 300; 9.70(d, 1H); 8.55(d, 1H); 8.30(dd, 1H); 8.22(d, 1H); Cl, 15.24 1635; 1590; 272; 237 8.21(s, 1H); 8.17(d, 1H); 7.86(dd, 1H); 7.84(d, 1H); Found C, 64.59; H, 3.95; N, 5.94; 1535 7.70(dd, 1H); 7.54(dd, 2H); 7.47–7.36(m, 3H); 5.78(d, 1H); Cl, 15.03 3.74(s, 3H). 68 3300; 1635; 338; 337; 255; 233; 232; 9.18(d br, 1H); 8.35(d, 2H); 8.20(s, 1H); 8.13(d, 1H); 1590; 1530; 204 8.07(d, 1H); 7.81(dd, 1H); 7.63–7.51(m, 4H); 1495; 770 7.44(d, 2H); 7.38(dd, 2H); 7.28(dd, 1H); 5.08(dt br, 1H); 2.89(d, 2H); 1.60(s br, 2H). 69 Calcd. C, 78.71; H, 6.08; N, 11.01 3490; 3380; 381(M+.); 352; 247; 9.20(d, 1H); 7.87(m, 1H); 7.70(d, 2H); Found C, 78.45; H, 6.10; N, 10.96 3260; 1630; 219; 218 7.59–7.26(m, 11H); 5.08(dt, 1H); 4.80(s br, 2H); 2.81(dq, 2H); 1600 0.95(t, 3H). 70 Calcd. C, 74.90; H, 5.28; N, 6.99; 3230; 1640; 400(M+.); 371; 266; 9.37(d, 1H), 8.10(d, 1H); 7.85(dd, 1H); Cl, 8.84 1550 238; 203 7.75–7.35(m, 12H); 5.07(dt, 1H); 1.80(dq, 2H); 0.98(t,, 3H). Found C, 74.88; H, 5.25; N, 6.98; Cl, 8.92 71 Calcd. C, 67.42; H, 4.75; N, 6.29; 3240; 1640; 444/446(M+.); 415/417; 9.35(d, 1H); 8.10(d, 1H); 7.85(dd br, 1H); Br, 17.94 1545 310/312; 203 7.70–7.30(m, 12H); 5.05(dt, 1H); 1.81(dq, 2H); 0.99(t, 3H). Found C, 67.57; H, 4.80; N, 6.31; Br, 18.00 72 Calcd. C, 82.07; H, 6.36; N, 7.36 3240; 381(MH)+; TSP, 9.24(d, 1H); 8.29(d, 2H); 8.14(d, 1H); 8.01(s, 1H); Found C, 82.00; H, 6.36; N, 7.33 1630; 1590; ammonium 7.96(d, 1H); 7.81(dd, 1H); 7.64–7.51(m, 4H); 1545 acetate(50mM)/ 7.47–7.36(m, 4H); 7.29(dd, 1H); 4.90(dd, 1H); acetonitrile 2.19–2.02(m, 1H); 1.08(d, 3H); 0.80(d, 3H). 60:40 as eluent; source 250° C. 73 Calcd. C, 81.94; H, 6.05; N, 7.64 3320; 1635; 366(M+.); 337; 232; 204 9.24(d, 1H); 8.30(d, 2H); 8.14(d, 1H); 8.09(s, 1H); Found C, 79.33; H, 5.82; N, 7.34 1590; 1535 8.02(d, 1H); 7.82(dd, 1H); 7.63–7.51(m, 4H); 7.46(d, 2H); 7.38(dd, 2H); 7.24(dd, 1H); 5.14(dt, 1H); 1.95–1.78(m, 2H); 0.98(t, 3H). 74 Calcd. C, 81.94; H, 6.05; N, 7.64 3280; 1637; 366(M+.); 337; 232; 204 9.24(d, 1H); 8.30(d, 2H); 8.14(d, 1H); 8.09(s, 1H); Found C, 82.08; H, 6.09; N, 7.59 1590; 1540 8.02(d, 1H); 7.82(dd, 1H); 7.63–7.51(m, 4H); 7.46(d, 2H); 7.38(dd, 2H); 7.24(dd, 1H); 5.14(dt, 1H); 1.95–1.78(m, 2H); 0.98(t, 3H). 75 Calcd. C, 72.45; H, 4.62; N, 6.76 3280; 1740; 414(M+.); 355; 250; 222 9.75(d, 1H); 8.28(dd, 2H); 8.21(dd, 1H); 8.2(s, 1H); Found C, 72.28; H, 4.59; N, 6.79 1650; 1630; 7.95(dd, 1H); 7.77(ddd, 1H); 7.61–7.50(m, 5H); 1550 7.47–7.36(m, 3H); 5.80(d, 1H); 3.74(s, 3H). 76 Calcd. C, 74.60; H, 6.51; N, 6.96 1740; 1665; 402(M+.); 238; 210 9.61(d, 1H); 8.11(d, 1H); 7.99(d, 1H); 7.75(dd, 1H); Found C, 74.32; H, 6.50; N, 6.90 1595; 1535 7.59(dd, 1H); 7.50(d, 2H); 7.47–7.35(m, 4H); 5.74(d, 1H); 3.72(s, 3H); 2.90(tt, 1H); 2.00–1.20(m, 10H). 77 Calcd. C, 69.69; H, 4.45; N, 6.50 3290; 1745; 431(MH+)^(•) 9.71(d, 1H); 8.37(s, 1H); 8.30–8.15(m, 3H); Found C, 69.81; H, 4.45; N, 6.54 1660; 1640; 7.85(dd, 1H); 7.69(dd, 1H); 7.63–7.38(m, 8H); 5.79(d, 1H); 1585; 1530 3.74(s, 3H). 78 Calcd. C, 69.69; H, 4.44; N, 6.50 3290; 1745; 431(MH+); TSP, 9.70(d, 1H); 8.24(d, 1H); 8.14(d, 1H); 7.87(dd, 1H); Found C, 69.90; H, 4.42; N, 6.57 1660; 1600; ammonium 7.77(s, 1H); 7.76–7.62(m, 3H); 7.58–7.48(m, 4H); 1520 acetate(0.1M)/ 7.44–7.34(m, 3H); 5.80(d, 1H); 3.72(s, 3H). acetonitrile 60:40 as eluent; source 250° C. 79 Calcd. C, 78.51; H, 5.80; N, 7.32 3310; 3110; 382(M+.); 353; 264; 9.80(s, 1H); 9.11(d, 1H); 8.00–7.94(m, 3H); Found C, 78.55; H, 5.82; N, 7.26 1645; 1575; 247; 219 7.61–7.42(m, 8H); 7.38(dd, 2H); 7.28(dd, 1H); 5.06(dt, 1H); 1535 1.82(ddq, 2H); 0.97(t, 3H). 80 Calcd. C, 71.36; H, 4.88; N, 6.16 3320; 1760; 455(MH)+^(•) 9.74(d, 1H); 8.24(dd, 2H); 8.17(s, 1H); 8.08(dd, 1H); Found C, 71.39; H, 4.88; N, 6.17 1735; 1650; 7.70–7.50(m, 7H); 7.46–7.35(m, 3H); 5.75(d, 1H); 1530 3.75(s, 3H). 81 Calcd. C, 72.80; H, 4.89; N, 6.79 3360; 3300; 413(MH)+^(•) 9.69(d, 1H); 9.68(s, 1H); 8.49(d, 2H); 8.12(s, 1H); Found C, 73.24; H, 5.00; N, 6.42 1745; 1650; 7.64–7.35(m, 10H); 7.18(d, 1H); 5.79(d, 1H); 3.77(s, 3H). 1600; 1560; 82 Calcd. C, 64.53; H, 3.90; N, 6.02 3240; 1740; 464(M+.); 405; 300; 10.68(d, 1H); 8.25(d, 1H); 8.14(d, 1H); 7.88(dd, 1H); Found C, 64.71; H, 3.96; N, 6.00 1645; 1595; 272; 237 7.82(d, 1H); 7.78(s, 1H); 7.74(dd, 1H); 7.74(d, 1H), 1550 7.62(dd, 1H); 7.51(d, 2H); 7.44–7.33(m, 3H); 6.78(d, 1H); 3.74(s, 3H). 83 Calcd. C, 66.89; H, 4.72; N, 6.24; 3180; 1750; 412(M+.); 353; 232; 204 9.62(d, 1H); 8.28(d, 2H); 8.22(d, 1H); 8.16(d, 1H); Cl, 7.90 1660; 1645; 8.11(s, 1H); 7.86(dd, 1H); 7.68(dd, 1H); 7.61–7.51(m, 3H); Found C, 66.53; H, 4.74; N, 6.10; 1610; 1535; 7.30(d, 2H); 6.80(d, 2H); 5.61(d, 1H); 3.71(s, 3H). Cl, 7.48 1510 84 Calcd. C, 84.03; H, 5.35; N, 6.76 3210; 1640; 414(M+.); 337; 232; 204 9.79(d, 1H); 8.30(dd, 2H); 8.15(s, 1H); 8.12(d, 1H); Found C, 83.27; H, 5.64; N, 7.05 1590; 1525 8.02(d, 1H); 7.81(dd, 1H); 7.63–7.26(m, 14H); 6.52(d, 1H). 85 Calcd. C, 78.51; H, 5.80; N, 7.33 3370; 1625; 382(M+.); 264; 247; 219 9.80(s, 1H); 9.11(d, 1H); 8.00–7.94(m, 3H); Found C, 78.49; H, 5.84; N, 7.26 1525 7.61–7.42(m, 8H); 7.38(dd, 2H); 7.28(dd, 1H); 5.06(dt, 1H); 1.82(ddq, 2H); 0.97(t, 3H). 86 Calcd. C, 78.51; H, 5.80; N, 7.33 3270; 1650; 382(M+.); 264; 247; 219 9.80(s, 1H); 9.11(d, 1H); 8.00–7.94(m, 3H); Found C, 78.55; H, 5.84; N, 7.30 1630; 1570; 7.61–7.42(m, 8H); 7.38(dd, 2H); 7.28(dd, 1H); 5.06(dt, 1H); 1535 1.82(ddq, 2H); 0.97(t, 3H). 87 Calcd. C, 72.80; H, 4.89; N, 6.79 3360; 1735; 412(M+.); 353; 248; 219 9.85(s, 1H); 9.63(d br, 1H); 7.97(m, 3H); 7.89(d br, 1H); Found C, 72.12; H, 4.88; N, 6.63 1625; 1530 7.62–7.34(m, 10H); 5.75(d, 1H); 3.76(s, 3H). 88 Calcd. C, 78.96; H, 6.37; N, 10.62 3320; 1640; 395(M+.); 232; 204 9.15(d, 1H); 9.30(d, 2H); 9.18(dd, 2H); 8.06(s, 1H); Found C, 78.63; H, 6.39; N, 10.65 1590; 1525; 7.80(t, 1H); 7.70–7.20(m, 9H); 5.30(dt, 1H); 770 2.75(dd, 1H); 2.45(dd, 1H); 2.70(s, 6H). 89 Calcd. C, 76.26; H, 5.66; N, 10.26 3280; 1660; 409(M+.); 337; 232; 204 9.40(d, 1H); 8.26(d, 2H); 8.22(d, 1H); 8.12(d, 1H); Found C, 75.74; H, 5.66; N, 10.06 1635; 1590 8.05(s, 1H); 7.81(dd, 1H); 7.62(dd, 1H); 7.59–7.49(m, 5H); 7.43–7.33(m, 3H); 6.15(d, 1H); 3.00(s, 3H); 2.90(s, 3H). 90 Calcd. C, 75.57; H, 5.02; N, 11.02 3360; 3270; 381(M+.); 337; 232; 204 9.40(d, 1H); 8.31(d, 2H); 8.16(s, 1H); 8.15(d, 1H); Found C, 75.23; H, 5.12; N, 10.88 1680; 1650; 8.12(d, 1H); 7.81(dd, 1H); 7.78(s br, 1H); 7.64–7.50(m, 6H); 1600 7.41–7.30(m, 3H); 7.23(s br, 1H); 5.71(d, 1H). 91 Calcd. C, 77.22; H, 5.79; N, 9.65 3220; 1660; 436(MH+); TSP, 9.48(d, 1H); 8.27(d, 2H); 8.23(d, 1H); 8.12(d, 1H); Found C, 76.91; H, 5.87; N, 9.56 1620; 1590 ammonium 8.06(s, 1H); 8.02(dd, 1H); 7.63(dd, 1H); 7.60–7.50(m, 5H); acetate(0.1M)/ 7.45–7.33(m, 3H); 5.92(d, 1H); 3.82–3.71(m, 1H); acetonitrile 3.53–3.26(m, 2H); 3.16–3.08(m, 1H); 1.98–1.68(m, 4H). 60:40 as eluent; source 250° C. 92 Calcd. C, 68.82; H, 4.57; N, 6.69; 1740; 1670; 382(M+.); 337; 204 9.64(d, 1H); 8.28(d, 2H); 8.22(d, 1H); 8.16(d, 1H); Cl, 8.46 1635; 1610; 8.13(s, 1H); 7.84(dd, 1H); 7.66(dd, 1H); 7.62–7.51(m, 5H); Found C, 68.42; H, 4.60; N, 6.56; 1540 7.46–7.34(m, 3H); 5.70(d, 1H). Cl, 8.22 *oil mull; ^(•)FAB POS, thioglycerol matrix, Xe gas, 8KeV, source 50° C.

EXAMPLE 93 (R,S)-N-[α-(Methoxycarbonyl)benzyl]-2-(p-chlorophenyl)quinoline-4-carboxamide

2 g (7.0 mmol) of 2-(p-chlorophenyl)quinoline-4-carboxylic acid and 1.7 ml (15.4 mmol) of N-methylmorpholine were dissolved, under nitrogen athmosphere, in 50 ml of dry THF.

The solution was cooled to −20° C. and 0.91 ml (7.0 mmol) of isobutyl chloroformate were added. After 20 minutes, 2.12 g (10.5 mmol) of methyl (R,S) phenylglycinate hydrochloride and 1.3 ml (11.9 mmol) of N-methylmorpholine, dissolved in 30 ml of dry THF, were added and the reation mixture was stirred at room temperature overnight.

5 ml of H₂O were added and the reaction mixture was evaporated in vacuo to dryness. The residue was dissolved in Et₂O, washed with a saturated solution of NaHCO₃, separated, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/isopropyl ether 7:3 to afford 0.9 g of crude product, which was recrystallized three times with iPrO₂/toluene to yield 0.5 g of the title compound.

C₂₅H₁₉ClN₂O₃M.P.=170-172° C. M.W.=430.90Elemental analysis: Calcd. C, 69.72; H. 4.45; N, 6.50. Found C, 69.82; H, 4.47; N, 6.48.I.R. (KBr): 3280; 1740; 1670; 1635; 1590; 1530 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): 9.71 (d, 1H); 8.32 (d, 2H); 8.21 (d, 1H); 8.13 (d, 1H); 8.13 (s, 1H); 7.85 (dd, 1H); 7.67 (dd, 1H); 7.63 (d, 2H); 7.53 (dd, 2H); 7.46-7.38 (m, 3H); 5.79 (d, 1H); 3.74 (s, 3H). MS (EI; source 200° C.; 70 eV; 200 μA): 430 (M+.); 371; 266; 238; 203.

EXAMPLE 94 (R)-N-[α-(Methoxycarbonyl)-4-methoxybenzyl]-2-phenylquinoline-4-carboxamide

0.62 g (1.5 mmol) of (R)-N-[α-(methoxycarbonyl)-4-hydroxybenzyl]-2-phenylquinoline-4-carboxamide (compound of Ex. 83) were dissolved in 30 ml of dry acetone and 2 ml of dry DMF; 0.14 g (0.75 mmol) of K₂CO₃ were added and the reaction mixture was stirred for 30 minutes.

0.093 ml (1.5 mmol) of methyl iodide were added at room temperature and the reaction mixture was heated at 40° C. for 4 hours. 0.104 g (0.75 mmol) of K₂CO₃ and 0.093 ml (1.5 mmol) of methyl iodide were added again, and the mixture refluxed for additional 6 hours.

The mixture was evaporated in vacuo to dryness, dissolved in EtOAc and washed with H₂O. The organic layer, dried over Na₂SO₄, was evaporated in vacuo to dryness. The residue was recrystallized from Et₂O to yield 0.45 g of the title compound.

C₂₆H₂₂N₂O₄M.P.=160-162° C. M.W.=426.48Elemental analysis: Calcd. C, 73.22; H, 5.20; N, 6.57. Found C, 73.01; H, 5.20; N, 6.48.I.R. (KBr): 3210; 1750; 1635; 1625; 1590; 1530; 1515 cm⁻¹ 300 MHz ¹H-NMR (DMSO-d₆): 9.65 (d, 1H); 8.28 (d, 2H); 8.21 (d, 1H); 8.14 (d, 1H); 8.10 (s, 1H); 7.84 (dd, 1H); 7.67 (dd, 1H); 7.61-7.49 (m, 3H); 7.44 (d, 2H); 6.98 (d, 2H); 4.70 (d, 1H); 3.79 (s, 3H); 3.76 (s, 3H). MS (EI; source 200° C.; 70 eV; 200 IA): 426 (M+.); 367; 232; 204.

EXAMPLE 95 (R,S)-N-[α-(Methoxycarbonyl)-α-(methyl)benzyl]-N-methyl-2-phenylquinoline-4-carboxamide hydrochloride

0.50 g (1.3 mmol) of (R,S)-N-[α-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (compound of Ex. 4) were dissolved, under nitrogen athmosphere, in 10 ml of dry DMF.

The solution was cooled to 0° C. and 0.052 g (1.3 mmol) of NaH (60%) were added; after 20 minutes at 0° C. the temperature was raised to r.t. and 0.09 ml (1.4 mmol) of

MeI were added. The reation mixture was stirred at room temperature overnight, then the procedure was repeated by adding additional 0.052 g (1.3 mmol) of NaH (60%) and 0.1 ml (1.6 mmol) of MeI.

After 6 hours at room temperature, 10 ml of saturated solution of NH₄Cl were added and the reaction mixture was evaporated in vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with water; the organic layer was separated, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 3:2 containing 0.5% of conc. NH₄OH to afford 0.18 g of a crude product which was dissolved in Et₂O and treated with HCl/Et₂O to yield 0.15 g of the title compound.

C₂₇H₂₄N₂O₃.HCl M.W.=460.96 I.R. (KBr): 1745; 1640; 1610 cm⁻¹. MS (EI; source 200° C.; 70 eV; 200 μA): 424 (M+.); 365; 232; 204.

EXAMPLE 96 (R,S)-N-[α-(Methylcarbonyl)benzyl]-2-phenylquinoline-4-carboxamide

0.27 ml (3.1 mmol) of oxalyl chloride were dissolved, under nitrogen athmosphere, in 2.3 ml of dry CH₂Cl₂.

The solution was cooled to −55° C. and 0.22 ml (3.1 mmol) of DMSO, dissolved in 0.7 ml of dry CH₂Cl₂, were added dropwise maintaining the temperature below −50° C. The reaction was stirred at −55° C. for 7 minutes then 0.97 g (2.5 mmol) of (R,S)-N-[α-(1-hydroxyethyl)benzyl]-2-phenylquinoline-4-carboxamide (compound of Ex. 17), dissolved in 25 ml of dry CH₂Cl₂, were added keeping the temperature between −50 and −55° C.

After 30 minutes at −55 IC, 1.9 ml (13.6 mmol) of TEA were added without exceeding −40° C., then the reaction mixture was allowed to reach room temperature and stirred for additional 15 minutes.

The reaction was quenched with 5 ml of H₂O and extracted with CH₂Cl₂; the organic layer was washed with H₂O, 20% citric acid, saturated solution of NaHCO₃ and brine; the organic layer was separated, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 70:30 containing 0.5% of conc. NH₄OH to afford 0.64 g of a crude product which was triturated with warm i-Pr₂O/1-PrOH 2:1, filtered, washed and dried to yield 0.5 g of the title compound.

C₂₅H₂₀N₂O₂M.P.=160-161° C. M.W.=380.45 Elemental analysis: Calcd. C, 78.93; H, 5.30; N, 7.36.Found C, 79.01; H, 5.31; N, 7.27.I.R. (KBr): 3400; 3265; 1725; 1660; 1640; 1592 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): 9.60 (d, 1H); 8.29 (d, 2H); 8.17 (d, 1H); 8.14 (d, 1H); 8.12 (s, 1H); 7.82 (dd, 1H); 7.65 (dd, 1H); 7.61-7.51 (m, 5H); 7.48-7.36 (m, 3H); 2.19 (s, 3H). MS (EI; source 200° C.; 70 eV; 200 μA): 380 (M+.); 337; 232; 204.

EXAMPLE 97 (R,S)-N-[α-(2-Hydroxyethyl)benzyl]-2-phenylquinoline-4-carboxamide

0.7 g (1.7 mmol) of (R,S)-N-[α-(methoxycarbonylmethyl)benzyl]-2-phenylquinoline-4-carboxamide (compound of Ex. 15) were dissolved, under nitrogen athmosphere, in 50 ml of t-BuOH and 2 ml of MeOH.

60 mg (1.6 mmol) of NaBH₄ were added in 15 minutes to the boiling solution. The reaction mixture was refluxed for 6 hours, quenched with 5 ml of saturated solution of NH₄Cl and then evaporated in vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with brine; the organic layer was separated, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with Et₂O containing 0.5% of conc. NH₄OH and then crystallized from i-PrOH to yield 0.19 g of the title compound.

C₂₅H₂₂N₂O₂M.P.=167-169° C. M.W.=382.47 Elemental analysis: Calcd. C, 78.52; H, 5.80; N, 7.32.Found C, 78.49; H, 5.79; N, 7.29. I.R. (KBr): 3360; 1650; 1592 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): 9.30 (d, 1H); 8.31 (d, 2H); 8.13 (d, 1H); 8.10 (s, 1H); 8.03 (d, 1H); 7.81 (dd, 1H); 7.64-7.51 (m, 4H); 7.46 (d, 2H); 7.39 (dd, 2H); 7.29 (dd, 1H); 5.30 (dt, 1H); 4.61 (t, 1H); 3.61-3.41 (m, 2H); 2.11-1.86 (m, 2H). MS (EI; source 200° C.; 70 eV; 200 μA): 382 (M+.); 337; 232; 204.

EXAMPLE 98 (S)-N-(α-Ethylbenzyl)-3-(2-dimethylaminoethoxy)-2-phenylquinoline-4-carboxamide hydrochloride

0.62 g (1.6 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 30 ml of dry DMF.

0.58 g (4.0 mmol) of dimethylaminoethylchloride hydrochloride and 0.56 g (4.0 mmol) of K₂CO₃ were added and the reaction mixture was refluxed for 20 hours.

The K₂CO₃ was filtered off and the mixture was evaporated in vacuo to dryness, dissolved in AcOEt and washed with H₂O and with 20% citric acid. The aqueous layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The residue was flash chromatographed on 230-400 mesh silica gel, eluting with CH₂Cl₂/MeOH 98:2 containing 0.4% of conc. NH₄OH and then with CH₂Cl₂/MeOH 86:10 containing 0.6% of conc. NH₄OH to yield 85 mg of a crude product which was dissolved in EtOAc and treated with HCl/Et₂O to obtain 75 mg of the title compound.

C₂₉H₃₁N₃O₂.HCl M.P.=70° C. dec. M.W.=490.05I.R. (nujol): 3600; 3100; 1650; 1550 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): 10.28 (s br, 1H); 9.50 (d, 1H); 8.10 (d, 1H); 7.96 (dd, 2H); 7.78 (m, 1H); 7.67-7.61 (m, 2H); 7.61-7.51 (m, 3H); 7.49-7.39 (m, 4H); 7.33 (dd, 1H); 5.08 (dt, 1H); 3.90 (t, 2H); 2.96 (dt, 2H); 2.49 (s, 6H); 1.85 (m, 2H); 0.97 (t, 3H). MS (FAB POS, thioglycerol matrix, Xe gas, 8 KeV, source 50° C.): 454 (MH+)

EXAMPLE 99 (S)-N-(α-Ethylbenzyl)-3-acetylamino-2-phenylquinoline-4-carboxamide

0.40 g (1.05 mmol) of (S)-N-(α-Ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide (compound of Ex. 69) were heated in 25 ml of acetic anhydride at 70° C. for 1 hour and then at 100° C. for additional 3 hours.

The reaction mixture was then evaporated in vacuo to dryness and the residue dissolved in EtOAc; the solution was washed with water, saturated solution of NaHCO₃, brine, dried over Na₂SO₄ and evaporated in vacuo to dryness.

The crude product (0.39 g) was purified by silica gel flash column chromatography, eluting with a mixture of hexane/EtOAc/conc. NH₄OH, 70:30:0.5, respectively, to afford 0.2 g of a pure compound which was recrystallized from acetone to yield 0.14 g of the title compound.

C₂₇H₂₅N₃O₂M.P.=268-269° C. M.W.=423.52Elemental analysis: Calcd. C, 76.57; H, 5.95; N, 9.92.Found C, 76.38; H, 5.98; N, 9.90.I.R. (KBr): 3230; 1670; 1640; 1555; 1525 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): 9.65 (s, 1H); 9.05 (d, 1H); 8.10 (d, 1H); 7.80 (t, 1H); 7.70-7.50 (m, 4H); 7.45-7.20 (m, 8H); 5.08 (dt, 1H); 1.85 (m, 2H); 1.60 (s, 3H); 0.97 (t, 3H). MS (EI; source 200° C.; 70 eV; 200 μA): 423 (M+.); 381; 334; 289; 261; 247; 218.

EXAMPLE 100 (−)-(S)-N-(α-Ethylbenzyl)-3-(3-dimethylaminopropoxy)-2-phenylquinoline-4-carboxamide hydrochloride

1.2 g (3.1 mmol) of (−)-(S)-N-(α-Ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 15 ml of dry THF. 1.0 g (8.2 mmol) of 3-dimethylaminopropylchloride, dissolved in 10 ml of Et₂O, 1.3 g (9.4 mmol) of K₂CO₃ and 0.16 g of KI were added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 2 hours.

Further 0.77 g (6.3 mmol), 1.0 g (8.2 mmol), 0.6 g (4.9 mmol) and additional 0.6 g (4.9 mmol) of 3-dimethylaminopropylchloride, dissolved each time in 10 ml of Et₂O, and some KI were added every 12 hours and the reaction refluxed.

The K₂CO₃ was filtered off and the mixture was evaporated in-vacuo to dryness, dissolved in EtOAc and washed with H₂O and with 20% citric acid. The aqueous layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness.

The residue was flash chromatographed on 230-400 mesh silica gel, eluting with CH₂Cl₂/MeOH 95:5 containing 0.5% of conc. NH₄OH to yield 0.9 g of a crude product which was dissolved in EtOAc and treated with HCl/Et₂O to obtain 0.62 g of the title compound.

C₃₀H₃₃N₃O₂.HCl M.P.=108° C. dec. M.W.=504.08 [α]_(D) ²⁰-16.0 (c=0.5, MeOH) I.R. (KBr): 3400; 3080; 1655; 1545 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 10.55 (s br, 1H); 9.35 (d, 1H); 8.09 (d, 1H); 7.92 (dd, 2H); 7.76 (ddd, 1H); 7.65-7.51 (m, 5H); 7.48-7.40 (m, 4H); 7.31 (dd, 1H); 5.10 (dt, 1H); 3.72-3.62 (m, 2H); 2.75-2.60 (m, 2H); 2.58 (d, 3H); 2.56 (d, 3H); 1.90-1.67 (m, 4H); 1.00 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 467 (M+.); 466; 395; 58.

EXAMPLE 101 (−)-(S)-N-(α-Ethylbenzyl)-3-[2-(1-phthaloyl)ethoxy]-2-phenylquinoline-4-carboxamide hydrochloride

1.9 g (5.0 mmol) of (−)-(S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 20 ml of dry THF.

3.8 g (14.9 mmol) of 2-phthalimidoethylbromide, dissolved in 15 ml of THF, 2.0 g (14.5 mmol) of K₂CO₃ and 0.25 g of KI were added and the reaction mixture was stirred at room temperature for 2.5 hours and then refluxed for 2 hours.

1.9 g (7.4 mmol) of 2-phthalimidoethylbromide and some KI were added and the reaction was refluxed for additional 3.5 hours.

0.5 g (2.0 mmol) of 2-phthalimidoethylbromide and some KI were added again and the mixture was refluxed for 5 hours.

The K₂CO₃ was filtered off and the mixture was evaporated in-vacuo to dryness, dissolved in CH₂Cl₂ and washed with H₂O. The organic layer was dried over Na₂SO₄ and evaporated in-vacuo to dryness.

The residue was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/EtOAc 80:20 containing 0.5% of conc. NH₄OH and then hexane/EtOAc 60:40 containing 0.5% of conc. NH₄OH to afford 2.6 g of a purified product which was triturated with iPr₂O to yield 2.5 g of the title compound.

C₃₅H₂₉N₃O₄M.P.=172-175° C. M.W.=555.64 [α]_(D) ²⁰−16.3 (c=0.5, MeOH) I.R. (KBr): 3280; 3060; 2960; 1780; 1715; 1660; 1530 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.27 (d, 1H); 8.03 (d, 1H); 7.92-7.84 (m, 4H); 7.78-7.69 (m, 3H); 7.60-7.53 (m, 2H); 7.46-7.38 (m, 4H); 7.27 (dd, 1H); 7.13-7.04 (m, 3H); 4.96 (dt, 1H); 3.92-3.78 (m, 2H); 3.72-3.55 (m, 2H); 1.78 (dq, 2H); 0.93 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 555 (M+.), 526, 421, 174.

EXAMPLE 102 (−)-(S)-N-(α-Ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide hydrochloride

2.2 g (3.9 mmol) of (−)-(S)-N-(α-ethylbenzyl)-3-[2-(1-phthaloyl)ethoxy]-2-phenyl quinoline-4-carboxamide hydrochloride (compound of Ex. 101) were dissolved in 150 ml of 96% EtOH and 0.38 ml (7.8 mmol) of hydrazine hydrate were added to the boiling solution, which was then refluxed for 4 hours.

Further 0.4 ml (8.2 mmol), 0.2 ml (4.1 mmol), 0.2 ml (4.1 mmol), 0.4 ml (8.2 mmol) and 0.4 ml (8.2 mmol) of hydrazine hydrate were added every 12 hours and the reaction mixture was maintained refluxed.

The reaction mixture was then evaporated in-vacuo to dryness, dissolved in 20 ml H₂O, cooled and acidified with 10 ml conc. HCl.

The mixture was boiled for 1 hour and cooled; the phthalydrazide was filtered off. The aqueous layer was washed with EtOAc and then made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness.

The residue was flash chromatographed on 230-400 mesh silica gel, eluting with EtOAc/MeOH 96:4 containing 1.2% of conc. NH₄OH to afford a purified product which was dissolved in EtOAc and treated with HCl/Et₂O to yield 1.2 g of the title compound.

C₂₇H₂₇N₃O₂.HCl M.P.=119° C. dec. M.W.=462.00 [α]_(D) ²⁰=−19.4 (c=0.5, MeOH) I.R. (KBr): 3400; 3080; 1640; 1545 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.45 (d, 1H); 8.09 (d, 1H); 8.00 (dd, 1H); 7.94 (s br, 3H); 7.76 (ddd, 1H); 7.65-7.51 (m, 4H); 7.48-7.40 (m, 3H); 7.31 (dd, 1H); 5.09 (dt, 1H); 3.83 (t, 2H); 2.72 (m, 2H); 1.93-1.80 (m, 2H); 0.99 (t, 3H). MS (FAB POS, thioglycerol matrix; Xe gas, 8 keV; source 50° C.): 426 (MH+).

EXAMPLE 103 (+)-(S)-N-(α-Ethylbenzyl)-3-[2-(1-pyrrolidinyl)ethoxy]-2-phenylquinoline-4-carboxamide hydrochloride

2.0 g (5.2 mmol) of (−)-(S)-N-(α-Ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Ex. 85) were dissolved in 25 ml of dry THF.

1.0 g (7.5 mmol) of 2-pyrrolidinoethylchloride and 2.2 g (15.9 mmol) of K₂CO₃ were added and the reaction mixture was stirred at room temperature for 30 minutes and then refluxed; 1.1 g (8.2 mmol) of 2-pyrrolidinoethylchloride were added to the boiling solution which was refluxed overnight.

The K₂CO₃ was filtered off and the mixture was evaporated in-vacuo to dryness, dissolved in EtOAc and washed with H₂O and 20% citric acid. The aqueous layer was made alkaline with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness.

The residue was flash chromatographed on 230-400 mesh silica gel, eluting with CH₂Cl₂/MeOH 97:3 containing 0.5% of conc. NH₄OH to yield 1.8 g of a purified product which was dissolved in EtOAc and treated with HCl/Et₂O to yield 2.0 g of the title compound.

C₃₁H₃₃N₃O₂.HCl M.P.=110-115° C. (dec.) M.W.=516.08 [α]_(D) ²⁰=+4.5 (c=0.5, MeOH) I.R. (KBr): 3400; 3080; 1655; 1545 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 10.50 (s br, 1H); 9.50 (d, 1H); 8.10 (d, 1H); 7.96 (dd, 2H); 7.78 (ddd, 1H); 7.68-7.30 (m, 10H); 5.10 (dt, 1H); 3.90 (m, 2H); 3.20 (m, 2H); 3.00 (m, 2H); 2.65 (m, 2H); 1.95-1.65 (m, 6H); 1.94 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 479 (M+.); 478; 383; 97; 84.

EXAMPLE 104 (−)-(S)-N-(α-Ethylbenzyl)-3-(dimethylaminoacetylamino)-2-phenylquinoline-4-carboxamide

1.1 g (2.8 mmol) of (−)-(S)-N-(α-ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide (compound of Ex. 69) were dissolved, under nitrogen atmosphere, in 10 ml of warm toluene. 0.96 g (5.6 mmol) of chloroacetic anhydride, dissolved in 5 ml of toluene, were dropped and the solution was refluxed for 1 hour.

The reaction mixture was evaporated in-vacuo to dryness, suspended in 10 ml of CH₂Cl₂ and dropped in 5 ml of ice-cooled 28% Me₂NH/EtOH.

The solution was stirred at room temperature overnight, then 15 ml of 28% Me₂NH/EtOH were added and the reaction mixture was heated at 60° C. in a parr apparatus.

The mixture was evaporated in-vacuo to dryness, dissolved in 20% citric acid and washed with EtOAc. The aqueous layer was basified with 2 N NaOH and extracted with EtOAc; the organic layer was washed with brine, separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness to afford 1.4 g of the crude product

This product was triturated with warm i-Pr₂O to yield 0.86 g of the title compound.

C₂₉H₃₀N₄O₂M.P.=189-191° C. M.W.=466.59 [α]_(D) ²⁰=−63.1 (c=0.5, MeOH) I.R. (KBr): 3230; 3180; 1670; 1630; 1540 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.41 (s, 1H); 8.97 (d, 1H), 8.08 (d, 1H); 7.81 (dd, 1H); 7.70-7.59 (m, 4H); 7.49-7.26 (m, 8H); 5.00 (dt, 1H); 2.55 (s, 2H); 1.97 (s; 3H); 1.90-1.65 (m, 2H); 0.93 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 466 (M+.); 331; 58.

EXAMPLE 105 N-(α,α-Dimethylbenzyl)-3-hydroxy-2-phenylquinouline-4-carboxamide

2.0 g (7.5 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of CH₃CN.

1.02 g (7.5 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at −10° C.

1.71 g (8.3 mmol) of DCC, dissolved in 20 ml of CH₂Cl₂, were added dropwise and the solution was kept at −5°-0° C. for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 1.4 g of a crude product which was flash chromatographed on 230-400 mesh silica gel, eluting initially with hexane/EtOAc 9/1 and then hexane/EtOAc 8/2 to afford 0.4 g of the purified product which was recrystallized twice from i-PrOH to yield 0.15 g of the title compound.

C₂₅H₂₂N₂O₂M.P.=166-169° C. dec. M.W.=382.47I.R. (nujol): 3200; 1650; 1580; 1535 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.56 (s, 1H); 8.92 (s br, 1H); 8.00-7.94 (m, 3H); 7.76 (d br, 1H); 7.63-7.45 (m, 7H); 7.36 (dd; 2H); 7.24 (dd, 1H); 1.72 (s, 6H). MS (EI; source 180° C.; 70 V; 200 mA): 382 (M+.); 264; 247; 219; 119.

EXAMPLE 106 N-(α,α-Dimethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide

2.0 g (7.6 mmol) of 3-amino-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 70 ml of dry THF and 30 ml of CH₃CN.

1.02 g (7.6 mmol) of cumylamine and 1.12 g (8.3 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at −10° C.

1.72 g (8.3 mmol) of DCC, dissolved in 20 ml of CH₂Cl₂, were added dropwise and the solution was kept at −5°-0° C. for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 2.0 g of a crude product which was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/EtOAc 6/4 containing 1% of conc. NH₄OH to afford 0.9 g of the purified product which was recrystallized from hexane/EtOAc 1/1 and then from i-PrOH to yield 0.45 g of the title compound.

C₂₅H₂₃N₃O M.P.=166-168° C. M.W.=381.48I.R. (nujol): 3460; 3360; 3220; 1667; 1605; 1527 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.05 (s, 1H); 7.87 (dd, 1H); 7.74-7.68 (m, 3H); 7.60-7.42 (m, 7H); 7.37 (dd, 2H); 7.24 (dd, 1H); 4.74 (s, 2H); 1.71 (s, 6H). MS (EI; source 180° C.; 70 V; 200 mA): 381 (M+.); 263; 218; 119.

EXAMPLE 107 (−)-(S)-N-(α-Ethylbenzyl)-5-methyl-2-phenylquinoline-4-carboxamide

0.80 g (3.04 mmol) of 5-methyl-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 30 ml of dry THF and 12 ml of CH₃CN.

0.43 g (3.20 mmol) of (S)-(−)-α-ethylbenzylamine and 0.78 g (5.78 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at −10° C.

0.69 g (3.34 mmol) of DCC, dissolved in 5 ml of CH₂Cl₂, were added dropwise and the solution was kept at −5°-0° C. for 2 hours and then at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 10 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 1.15 g of a crude product which was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/EtOAc 6/2 containing 0.5% of conc. NH₄OH to afford 0.47 g of the purified product which was recrystallized from i-Pr₂O containing some drops of EtOAc to yield 0.36 g of the title compound as a white powder.

C₂₆H₂₄N₂O M.P.=189-192° C. M.W.=380.49 [α]_(D) ²⁰=−3.8 (c=0.5, MeOH) I.R. (KBr): 3280; 3070; 3020; 1635; 1545 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.20 (d, 1H); 8.23 (d, 2H); 7.93 (d, 1H); 7.78 (s, 1H); 7.20-7.70 (m, 10H); 5.00 (dt, 1H); 2.38 (s broad, 3H); 1.70-1.90 (m, 2H); 0.95 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 380 (M+.); 246; 218.

EXAMPLE 108 (R,S)-N-[α-(1-Hydroxyethyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide

Prepared as described in Ex. 1, starting from 11.08 g (39.33 mmol) of crude 3-methyl-2-phenylquinoline-4-carbonylchloride, 4.87 g (32.20 mmol) of 1-phenyl-2-hydroxypropylamine and 10.33 ml (74.14 mmol) of TEA in 150 ml of a 1:1 mixture of dry CH₂Cl₂ and CH₃CN.

The precipitated TEA hydrochloride was filtered off and the filtrate concentrated in-vacuo to dryness; the residue was dissolved in CH₂Cl₂ (100 ml) and washed with a sat. sol. of NaHCO₃, 20% citric acid and brine. The organic solution was dried over Na₂SO₄ and evaporated in-vacuo to dryness to obtain 13.23 g of an oil, which was crystallized from i-PrO₂ (100 ml) containing 6 ml of i-PrOH to yield 9.14 g of the title compound as an off-white solid.

C₂₆H₂₄N₂O₂M.P.=163-165° C. M.W.=396.49I.R. (nujol): 3400; 3260; 1635; 1580 cm⁻¹.

EXAMPLE 109 (R,S)-N-[α-(Methylcarbonyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide

Prepared as described in Example 96, starting from 3.25 g (25.60 mmol) of oxalyl chloride, 3.88 g (49.66 mmol) of DMSO, 8.2 g (20.68 mmol) of (R,S)-N-[α-(1-hydroxyethyl)benzyl]-3-methyl-2-phenylquinoline-4-carboxamide (compound of Ex. 108) and 15.72 ml (112.76 mmol) of TEA in 230 ml of dry CH₂Cl₂.

The reaction was quenched with 40 ml of H₂O and the organic layer separated and washed with 20% citric acid, sat. sol. NaHCO₃ and brine. The organic solution was dried over Na₂SO₄ and evaporated in-vacuo to dryness to afford 9.4 g of the crude title compound as an oil. This residual oil was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/ethyl acetate 70:30 containing 1% of conc. NH₄OH to afford 7.7 g of the purified product which was crystallized from a mixture of EtOAc/hexane 1:3 respectively, to yield 6.0 g of the pure title compound.

C₂₆H₂₂N₂O₂M.P.=156-158° C. M.W.=394.48I.R. (nujol): 3270; 3180; 1735; 1725; 1660; 1630; 1527; 1460 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.53 (d, 1H); 8.01 (d, 1H); 7.73 (dd, 1H); 7.62-7.35 (m, 12H); 5.97 (d, 1H); 2.30 (s br, 3H); 2.18 (s, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 394 (M+.); 352; 351; 246; 218; 217.

EXAMPLE 110 (R,S)-N-[α-(Ethyl)-4-pyridylmethyl]-2-phenylquinoline-4-carboxamide

4.12 g (16.52 mmol) of 2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 40 ml of dry CH₂Cl₂ and 30 ml of THF.

1.50 g (11.01 mmol) of 1-(4-pyridyl)-n-propyl amine and 2.23 g (16.52 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at 0° C.

3.41 g (16.52 mmol) of DCC, dissolved in 26 ml of dry CH₂Cl₂, were added dropwise and the solution was kept at 0° C. for 2 hours and then stirred at room temperature for 36 hours. The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in 100 ml of CH₂Cl₂ and washed with H₂O, 10% K₂CO₃, 5% citric acid and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 30 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 3.5 g of a crude product which was recrystallized three times from i-PrOH to yield 0.91 g of the title compound.

C₂₄H₂₁N₃O M.P.=218-219° C. M.W.=367.45I.R. (KBr): 3260; 3060; 1648; 1595; 1545; 1350 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.33 (d, 1H); 8.58 (d, 2H); 8.33 (dd, 2H); 8.15 (d, 1H); 8.14 (s, 1H); 8.03 (d, 1H); 7.82 (dd, 1H); 7.66-7.52 (m, 4H); 7.47 (d, 2H); 5.05 (dt, 1H); 1.85 (dq, 2H); 1.00 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 367 (M+.); 338; 232; 204.

EXAMPLE 111 (R,S)-N-[α-(Ethyl)-2-thienylmethyl]-2-phenylquinoline-4-carboxamide

1.40 g (8.00 mmol) of 1-(2-thienyl)-n-propyl amine hydrochloride and 2.45 ml (17.60 mmol) of TEA were dissolved, under nitrogen atmosphere, in 50 ml of dry CH₂Cl₂ and 30 ml of CH₃CN.

2.0 g (8.00 mmol) of 2-phenylquinoline-4-carboxylic acid and 1.30 g (9.60 mmol) of N-hydroxybenzotriazole (HOBT) were added.

2.48 g (12.00 mmol) of DCC, dissolved in 30 ml of dry CH₂Cl₂, were added dropwise and the solution was stirred at room temperature for 36 hours. 50 ml of 10% HCl were added and the solution stirred for aditional 2 hours. The precipitated dicyclohexylurea was filtered off and the organic layer washed with 10% citric acid and 10% K₂CO₃.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness. The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc/CH₂Cl₂ 80:15:0.5 to afford 2.0 g of a yellow oil which was crystallized from a mixture of toluene/hexane to yield 0.9 g of the pure title compound as white crystals.

C₂₃H₂₀N₂OS M.P.=134-137° C. M.W.=372.49I.R. (KBr): 3230; 3060; 1630; 1590; 1545 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆): δ 9.33 (d, 1H); 8.30 (dd, 2H); 8.15 (d, 1H); 8.13 (d, 1H); 8.08 (s, 1H); 7.84 (ddd, 1H); 7.68-7.51 (m, 4H); 7.44 (dd, 1H); 7.11 (d, 1H); 7.02 (dd, 1H); 5.33 (dt, 1H); 2.10-1.88 (m, 2H); 1.05 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 372 (M+.); 343; 232; 204.

EXAMPLE 112 (+)-(S)-N-(α-Ethylbenzyl)-3-dimethylaminomethyl-2-phenylquinoline-4-carboxamide hydrochloride

5.60 g (21.27 mmol) of 3-methyl-2-phenylquinoline-4-carboxylic acid were dissolved in 100 ml of dichloroethane.

7.60 g (42.50 mmol) of N-bromosuccinimide and 0.52 g (2.00 mmol) of dibenzoyl peroxide were added and the solution refluxed for 24 hours.

The reaction mixture was evaporated in-vacuo to dryness, suspended in 100 ml of 33% Me₂NH/EtOH and stirred overnight at room temperature. The solution was evaporated in-vacuo to dryness, dissolved in 50 ml of 20% K₂CO₃ and evaporated again in-vacuo to dryness. 50 ml of water were added to the residue and the solution, acidified with 37% HCl, was evaporated in-vacuo to dryness.

The crude residue and 10.8 ml (77.20 mmol) of TEA were dissolved in 50 ml of CH₂Cl₂, 50 ml of THF and 100 ml of CH₃CN.

3.00 g (22.20 mmol) of (S)-(−)-α-ethylbenzylamine, 0.78 g (5.78 mmol) of N-hydroxybenzotriazole (HOBT) and 11.9 g (57.90 mmol) of DCC were added and the solution was stirred at room temperature overnight.

The precipitated dicyclohexylurea was filtered off and the organic layer evaporated in-vacuo to dryness.

The brown oily residue was dissolved in 100 ml of CH₂Cl₂ and the precipitate was filtered off. The filtrate was extracted three times with 40% citric acid. The acqueous layer, basified with solid K₂CO₃, was extracted with CH₂Cl₂; the organic solution dried over Na₂SO₄ and evaporated in-vacuo to dryness afforded 10 g of a brown oil.

The crude product was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of i-Pr₂O/CH₂Cl₂ 9:1 to afford 2.5 g of a white solid which was dissolved in toluene and left overnight.

The DCU precipitated was filtered and the solution, treated with ethanolic HCl, was evaporated in-vacuo to dryness. The crude product was recrystallized from a mixture of toluene/EtOH to yield 0.7 g of the pure title compound as colourless crystals.

C₂₈H₂₉N₃O HCl M.P.=164-167° C. M.W.=460.02 [α]_(D) ²⁰=+25.3 (c=1, MeOH) I.R. (KBr): 3440; 3150; 3020; 2560; 2460; 1650; 1540 cm⁻¹. 300 MHz ¹H-NMR (DMSO-d₆, 353 K): δ 9.70 (s br, 1H); 8.10 (d, 1H); 7.85 (dd, 1H); 7.80 (s br, 1H); 7.70-7.10 (m, 12H); 5.15 (dt, 1H); 4.38-4.20 (m, 2H); 2.30 (s, 3H); 2.22 (s, 6H); 2-10-1.82 (m, 2H); 1.00 (t, 3H). MS (EI; source 180° C.; 70 V; 200 mA): 423 (M+.), 380, 288.

EXAMPLE 113 (S)-N-(α-Ethylbenzyl)-3-methyl-7-methoxy-2-phenylquinoline-4-carboxamide

Prepared as described in Ex. 1, starting from 1.27 g (4.09 mmol) of crude 3-methyl-7-methoxy-2-phenylquinoline-4-carbonylchloride, 0.55 g (4.09 mmol) of (S)-(−)-α-ethylbenzylamine and 1.71 ml (12.27 mmol) of TEA in 24 ml of dry CH₂Cl₂ and 1 ml of DMF to help solubility. The reaction mixture was stirred 12 hours at room temperture.

After being concentrated in-vacuo to dryness, the residue was dissolved in CH₂Cl₂ (30 ml) and washed with 10% NaHCO₃, 5% citric acid and brine. The organic solution was dried over Na₂SO₄ and evaporated in-vacuo to dryness to obtain 1.87 g of a crude product, which was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 70:30 to afford 0.350 g of a yellow oil.

C₂₇H₂₆N₂O₂M.W.=410.51I.R. (KBr): 3240; 2965; 2930; 1635; 1535; 1220 cm⁻¹.

EXAMPLE 114 (S)-N-(α-Ethylbenzyl)-3-amino-5-methyl-2-phenylquinoline-4-carboxamide

0.75 g (2.64 mmol) of 3-amino-5-methyl-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 30 ml of dry THF and 10 ml of CH₃CN.

0.38 g (2.83 mmol) of (S)-(−)-α-ethylbenzylamine and 0.69 g (5.18 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at −10° C.

0.61 g (2.97 mmol) of DCC, dissolved in 5 ml of CH₂Cl₂, were added dropwise and the solution was kept at −50-0° C. for 2 hours, heated at 50° C. for 4 hours and then left at room temperature overnight.

The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 10 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 0.86 g of a crude product which was flash chromatographed on 230-400 mesh silica gel, eluting with CH₂Cl₂/MeOH/conc. NH₄OH, 90:10:0.5 respectively, to afford 0.41 g of the title compound as an oil.

C₂₆H₂₅N₃O M.W.=395.50I.R. (KBr): 3480; 3390; 3230; 3020; 1635; 1615; 1545 cm⁻¹.

EXAMPLE 115 (S)-N-(α-Ethylbenzyl)-3-methoxy-5-methyl-2-phenylquinoline-4-carboxamide

1.29 g (4.40 mmol) of 3-methoxy-5-methyl-2-phenylquinoline-4-carboxylic acid were dissolved, under nitrogen atmosphere, in 40 ml of dry THF and 20 ml of CH₃CN.

0.63 g (4.62 mmol) of (S)-(−)-α-ethylbenzylamine and 1.13 g (8.36 mmol) of N-hydroxybenzotriazole (HOBT) were added and the reaction mixture was cooled at −10° C.

1.0 g (4.84 mmol) of DCC, dissolved in 5 ml of CH₂Cl₂, were added dropwise and the solution was kept at −5°-0° C. for 2 hours, heated at 50° C. for 4 hours and then left at room temperature overnight.

The precipitated dicyclohexylurea was filtered off and the solution evaporated in-vacuo to dryness. The residue was dissolved in CH₂Cl₂ and washed with H₂O, sat. sol. NaHCO₃, 5% citric acid, sat. sol. NaHCO₃ and brine.

The organic layer was separated, dried over Na₂SO₄ and evaporated in-vacuo to dryness; the residue was dissolved in 20 ml of CH₂Cl₂ and left overnight. Some more dicyclohexylurea precipitated and was filtered off. The solution was evaporated in-vacuo to dryness to obtain 2.45 g of a crude product which was flash chromatographed on 230-400 mesh silica gel, eluting with hexane/EtOAc 7:2 containing 0.5% of conc. NH₄OH, to afford 0.28 g of the title compound as an oil.

C₂₇H₂₆N₂O₂M.W.=410.52I.R. (KBr): 3270; 3020; 1635; 1535 cm⁻¹.

TABLE 6 Analytical data of compounds of Examples 93-115.

Melting [α]_(D) ²⁰ Molecular point, c = 0.5 Ex. Ar R R₁ R₂ R₃ R₄ R₅ * formula ° C. MeOH 93 Ph COOMe H H H H Ph(4-Cl) (R,S) C₂₅H₁₉ClN₂O₃ 170-172 — 94 Ph(4-OMe) COOMe H H H H Ph (R) C₂₆H₂₂N₂O₄ 160-162 95 Ph COOMe Me Me H H Ph (R,S) C₂₇H₂₄N₂O₃•HCl — 96 Ph COMe H H H H Ph (R,S) C₂₅H₂₀N₂O₂ 160-161 — 97 Ph CH₂CH₂OH H H H H Ph (R,S) C₂₅H₂₂N₂O₂ 167-169 — 98 Ph Et H H H OCH₂CH₂NMe₂ Ph (S) C₂₉H₃₁N₃O₂•HCl 70 dec.^(a)  —^(b) 99 Ph Et H H H NHCOMe Ph (S) C₂₇H₂₅N₃O₂ 268-269 −71.4 100 Ph Et H H H OCH₂CH₂CH₂NMe₂ Ph (S) C₃₀H₃₃N₃O₂•HCl 108 dec. −16.0 101 Ph Et H H H OCH₂CH₂phthalimido Ph (S) C₃₅H₂₉N₃O₄ 172-175 −16.3 102 Ph Et H H H OCH₂CH₂NH₂ Ph (S) C₂₇H₂₇N₃O₂•HCl 119 dec. −19.4 103 Ph Et H H H OCH₂CH₂pyrrolidino Ph (S) C₃₁H₃₃N₃O₂•HCl 110-115  +4.5 104 Ph Et H H H NHCOCH₂NMe₂ Ph (S) C₂₉H₃₀N₄O₂ 189-191 −63.1 105 Ph Me Me H H OH Ph — C₂₅H₂₂N₂O₂ 166-169 — 106 Ph Me Me H H NH₂ Ph — C₂₅H₂₃N₃O 166-168 — 107 Ph Et H H 5-Me H Ph (S) C₂₆H₂₄N₂O 189-192  −3.8 108 Ph CH(OH)Me H H H Me Ph (R,S) C₂₆H₂₄N₂O₂ 163-165 — 109 Ph COMe H H H Me Ph (R,S) C₂₆H₂₂N₂O₂ 156-158 — 110 4-Py Et H H H H Ph (R,S) C₂₄H₂₁N₃O 218-219 — 111 2-thienyl Et H H H H Ph (R,S) C₂₃H₂₀N₂OS 134-137 112 Ph Et H H H CH₂NMe₂ Ph (S) C₂₈H₂₉N₃O•HCl 164-167 +25.3 113 Ph Et H H 7-MeO Me Ph (S) C₂₇H₂₆N₂O₂ oil — 114 Ph Et H H 5-Me NH2 Ph (S) C₂₆H₂₅N₃O oil — 115 Ph Et H H 5-Me OMe Ph (S) C₂₇H₂₆N₂O₂ oil — ^(a)free base: mp = 141-143; ^(b)free base: [α]_(D) ²⁰ = −48.6 (c = 0.5, MeOH) 

1. A compound of formula (I):

in which: Ar is an optionally substituted phenyl group, or a naphthyl or C₅₋₇ cycloalkdienyl group, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N; R is linear or branched C₁₋₈ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkylalkyl, an optionally substituted phenyl group or a phenyl C₁₋₆ alkyl group, an optionally substituted five-membered heteroaromatic ring comprising up to four heteroatoms selected from O and N, hydroxy C₁₋₆ alkyl, amino C₁₋₆ alkyl, C₁₋₆ alkylaminoalkyl, di C₁₋₆ alkylaminoalkyl, C₁₋₆ acylaminoalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ alkylcarbonyl, carboxy, C₁₋₆ alkoxyxcarbonyl, C₁₋₆ alkoxycarbonyl C₁₋₆ alkyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, di C₁₋₆ alkylaminocarbonyl, halogeno C₁₋₆ alkyl; or is a group —(CH₂)_(p)— when cyclized onto Ar, where p is 2 or 3; R₁ and R₂, which may be the same or different, are independently hydrogen or C₁₋₆ linear or branched alkyl, or together form a —(CH2)n— group in which n represents 3, 4, or 5; or R₁ together with R forms a group —(CH₂)_(q)—, in which q is 2, 3, 4 or 5; R₃ and R₄, which may be the same or different are independently hydrogen, C₁₋₆ linear or branched alkyl, C₁₋₆ alkenyl, aryl, C₁₋₆ alkoxy, hydroxy, halogen, nitro, cyano, carboxy, carboxamido, sulphonamido, C₁₋₆ alkoxycarbonyl, trifluoromethyl, acyloxy, phthalimido, amino, mono- and di-C₁₋₆ alkylamino, —O(CH₂)_(r)—NT₂, in which r is 2, 3, or 4 and T is hydrogen or C₁₋₆ alkyl or it forms with the adjacent nitrogen a group

 in which V and V₁ are independently hydrogen or oxygen and u is 0, 1 or 2; —O(CH₂)_(s)—OW₂ in which s is 2, 3, or 4 and W is hydrogen or C₁₋₆ alkyl; hydroxyalkyl, aminoalkyl, mono-or di-alkylaminoalkyl, acylamino, alkylsulphonylamino, aminoacylamino, mono- or di-alkylaminoacylamino; with up to four R₃ substituents being present in the quinoline nucleus; or R₄ is a group —(CH₂)_(t)— when cyclized onto R₅ as aryl, in which t is 1, 2, or 3; R₅ is branched or linear C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₄₋₇ cycloalkylalkyl, optionally substituted aryl, wherein the optional substituent is one of hydroxy, halogen, C₁₋₆ alkoxy or C₁₋₆ alkyl, or an optionally substituted single or fused ring heterocyclic group, having aromatic character, containing from 5 to 12 ring atoms and comprising up to four hetero-atoms in the or each ring selected from S, O, N; X is O, S, or N—C≡N, or a pharmaceutically acceptable salt thereof. 